U.S. patent application number 15/508270 was filed with the patent office on 2017-10-05 for a salt of cephalosporin derivative, its crystalline solid and a method of manufacturing thereof.
This patent application is currently assigned to Shionogi & Co., Ltd.. The applicant listed for this patent is Shionogi & Co., Ltd.. Invention is credited to Takanori KURITA, Fumihiko MATSUBARA, Daiki NAGAMATSU.
Application Number | 20170281638 15/508270 |
Document ID | / |
Family ID | 55439902 |
Filed Date | 2017-10-05 |
United States Patent
Application |
20170281638 |
Kind Code |
A1 |
MATSUBARA; Fumihiko ; et
al. |
October 5, 2017 |
A SALT OF CEPHALOSPORIN DERIVATIVE, ITS CRYSTALLINE SOLID AND A
METHOD OF MANUFACTURING THEREOF
Abstract
The present invention provides an acid addition salt or a sodium
salt of a compound represented by the formula (IA): ##STR00001## or
their hydrate or a stable crystalline solid thereof. The salt or
the crystalline solid is extremely useful as an active ingredient
for the production of a pharmaceutical product.
Inventors: |
MATSUBARA; Fumihiko; (Osaka,
JP) ; KURITA; Takanori; (Hyogo, JP) ;
NAGAMATSU; Daiki; (Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shionogi & Co., Ltd. |
Osaka |
|
JP |
|
|
Assignee: |
Shionogi & Co., Ltd.
Osaka
JP
|
Family ID: |
55439902 |
Appl. No.: |
15/508270 |
Filed: |
September 3, 2015 |
PCT Filed: |
September 3, 2015 |
PCT NO: |
PCT/JP2015/075039 |
371 Date: |
March 2, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/185 20130101;
C07D 513/04 20130101; A61K 47/02 20130101; A61K 2800/84 20130101;
C07D 227/06 20130101; A61P 31/10 20180101; A61K 9/19 20130101; A61P
31/04 20180101; C07D 501/46 20130101; C07D 501/16 20130101; A61K
2300/00 20130101; A61K 31/546 20130101 |
International
Class: |
A61K 31/546 20060101
A61K031/546; C07D 227/06 20060101 C07D227/06; C07D 513/04 20060101
C07D513/04; A61K 31/185 20060101 A61K031/185; C07D 501/16 20060101
C07D501/16 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 4, 2014 |
JP |
2014-179853 |
Claims
1. An acid addition salt or a sodium salt of a compound represented
by the formula (IA): ##STR00009## or a hydrate thereof; provided
that the acid is 1) an acid having a substituted or unsubstituted
benzenesulfonic acid group or 2) a mixed acid comprising an acid
having a substituted or unsubstituted benzenesulfonic acid group
and an inorganic acid.
2. The acid addition salt or its hydrate according to claim 1.
3. The acid addition salt or its hydrate according to claim 1,
wherein the salt is formed from acid selected from 1)
p-toluenesulfonic acid, 2) benzenesulfonic acid, or 3) a
combination of p-toluenesulfonic acid or benzenesulfonic acid, and
an acid selected from sulfuric acid, hydrochloric acid and
hydrobromic acid.
4. The acid addition salt or its hydrate according to claim 1,
wherein the salt is 1) p-toluenesulfonic acid salt, or 3) the salt
formed from the combination of p-toluenesulfonic acid and sulfuric
acid.
5. The acid addition salt or its hydrate according to claim 4,
comprising about 1.0 to about 2.0 mole equivalents of
p-toluenesulfonic acid to the compound (IA).
6. The acid addition salt or its hydrate according to claim 4,
comprising about 1.0 to about 1.8 mole equivalents of
p-toluenesulfonic acid and about 0.1 to about 0.5 mole equivalents
of sulfuric acid to the compound (IA).
7. The acid addition salt or its hydrate according to claim 1,
which is a crystalline solid.
8. The acid addition salt or its hydrate according to claim 4,
which is a crystalline solid.
9. The acid addition salt or its hydrate according to claim 8,
which is a single phase crystal or a mixed crystal.
10. The hydrate according to claim 4, wherein the content of water
is about 12 to 17%.
11. The mixed crystal according to claim 8, comprising a single
phase crystal of 2 mole equivalents of p-toluenesulfonic acid salt
or its hydrate, and a single phase crystal containing 1 mole
equivalent of p-toluenesulfonic acid salt and 0.5 mole equivalents
of sulfuric acid salt or its hydrate.
12. The crystalline solid of the hydrate according to claim 7,
which is a mixed acid addition salt formed from 1.3 mole
equivalents of p-toluenesulfonic acid and 0.35 mole equivalents of
sulfuric acid.
13. The crystalline solid of the hydrate according to claim 7,
comprising about 20.2 to 23.2% of p-toluenesulfonic acid on an
anhydrous basis and, about 3.5 to 5.0% sulfuric acid on an
anhydrous basis.
14. The crystalline solid of the acid addition salt or its hydrate
according to claim 8, wherein the crystalline solid has at least
three peaks of diffraction angles (2.theta.) selected from:
8.2.degree..+-.0.2.degree., 10.1.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree. and 20.3.degree..+-.0.2.degree. in an
X-ray powder diffraction spectrum.
15. The crystalline solid according to claim 8, wherein the
crystalline solid has at least three peaks of diffraction angles
(2.theta.) selected from: 8.2.degree..+-.0.2.degree.,
8.9.degree..+-.0.2.degree., 10.1.degree..+-.0.2.degree.,
11.4.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree.,
19.9.degree..+-.0.2.degree., 20.3.degree..+-.0.2.degree.,
21.5.degree..+-.0.2.degree. and 26.2.degree..+-.0.2.degree. in an
X-ray powder diffraction spectrum.
16. The crystalline solid according to claim 8, wherein the
crystalline solid has at least three peaks of diffraction angles
(2.theta.) selected from: 8.2.degree..+-.0.2.degree.,
8.9.degree..+-.0.2.degree., 10.1.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 16.5.degree..+-.0.2.degree.,
17.1.degree..+-.0.2.degree., 17.9.degree..+-.0.2.degree.,
19.0.degree..+-.0.2.degree., 20.3.degree..+-.0.2 and
26.2.degree..+-.0.2.degree. in an X-ray powder diffraction
spectrum.
17. A pharmaceutical composition comprising the acid addition salt,
its hydrate or the crystalline solid thereof according to claim
1.
18. A process for preparing the crystalline solid of the acid
addition salt or its hydrate according to claim 8, characterized by
adding p-toluenesulfonic acid and sulfuric acid to a solution
containing the compound (IA).
19. The process for preparing the crystalline solid according to
claim 18, characterized by adding about 2.2 to 2.5 wt % of
p-toluenesulfonic acid monohydrate and about 5 to 6 wt % of
sulfuric acid to the column eluate containing the compound
(IA).
20. The sodium salt or its hydrate according to claim 1.
21. The sodium salt or its hydrate according to claim 20, which is
amorphous.
22. A pharmaceutical composition comprising the sodium salt or its
hydrate according to claim 20.
23. The pharmaceutical composition according to claim 22, which is
a lyophilized formulation.
24. A method for preparing a lyophilized formulation comprising a
sodium salt of the compound (IA) or its hydrate, characterized by
using the acid addition salt, its hydrate or the crystalline solid
thereof according to claim 1.
25. A method for preparing a lyophilized formulation comprising a
sodium salt of the compound (IA) or its hydrate, characterized by
freezing-drying a solution containing the acid addition salt, its
hydrate or the crystalline solid thereof according to claim 1 and
sodium hydrate.
26. The method for preparing the formulation according to claim 24,
wherein the acid addition salt is formed from 1) p-toluenesulfonic
acid, or 3) a combination of p-toluenesulfonic acid and sulfuric
acid.
27. A pharmaceutical composition containing the compound (IA), its
pharmaceutically acceptable salt, or a hydrate thereof, and further
sodium p-toluenesulfonate and/or sodium sulfate.
28. The pharmaceutical composition according to claim 27,
containing a sodium salt of the compound (IA) or its hydrate, and
further sodium p-toluenesulfonate and/or sodium sulfate.
Description
TECHNICAL FIELD
[0001] The present invention relates to a salt of cephalosporin
derivative, which is excellent in storage stability, solubility, an
operation of formulation or production process, its crystalline
solid and a manufacturing method thereof.
BACKGROUND ART
[0002] In the manufacturing process of pharmaceuticals, crystalline
forms having outstanding chemical or physical properties are
desired.
[0003] Patent Document 1 by the present applicant describes that a
cephalosporin derivative with a catechol group, having broad
antibacterial spectrum and a strong antibacterial activity against
particular .beta.-lactamase producing bacteria, is useful as a
therapeutic or prophylactic agent for infectious diseases. Although
the following compound (I-12):
##STR00002##
(hereinafter, it is also referred to as a compound (IA)) is
disclosed in a form of betaine in Example 12 of the patent
document, its sodium salt, its acid addition salt, and solvates
thereof are not specifically disclosed. Further, there is no
description at all about the crystal thereof.
PRIOR ART DOCUMENTS
Patent Document
[0004] [Patent Document 1] International Patent Application
Publication WO 2010/050468
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0005] A pharmaceutical active ingredient may have substantially
different physical properties depending on each solid form.
Differences in such physical properties may affect a preparation
method or administration method of the pharmaceutical active
ingredient or formulation, etc. As one means for improving the
physical properties, preparation of salts and crystalline solid are
known.
[0006] According to study and analysis of the present inventors,
the synthesized compound (IA) in Patent Document 1 is an amorphous.
Further it was found that using such compound as a pharmaceutically
active ingredient or its raw material is not always satisfactory in
terms of purity and storage stability, etc. Therefore, the
development of a suitable salt or crystalline solid of the compound
(IA) is desired.
[0007] Although the present inventors tried crystallization of the
compound (IA) by using a variety of acids or bases, they were not
successful. Especially for acids, they tried crystallization of the
acid addition salts of the compound (IA) under more than 1000
conditions using various acids such as hydrochloric acid, sulfuric
acid, formic acid, trifluoroacetic acid, phosphoric acid, benzoic
acid, methanesulfonic acid etc., while changing the solvent, the
temperature, and the crystallization method, but it was found that
crystallization thereof is very difficult. Also it was found that
solubility of the compound (IA) in water was very low. Therefore,
it is recognized that the improvement of the aqueous solubility of
the compound (IA) is also required in order to develop the compound
(IA) as an injection in particular.
Means for Solving the Problems
[0008] As a result of further extensive investigations to solve the
above problems, the present inventors have found that the compound
(IA) crystallized as stable acid addition salts by using acids
having a substituted or unsubstituted benzenesulfonic acid group
such as benzenesulfonic acid or p-toluenesulfonic acid. The
inventors have further found that the more stable crystals was
obtained as a mixed acid addition salt of the compound (IA) by
using acid having a substituted or unsubstituted benzenesulfonic
acid group together with inorganic acid. Further, the inventors
have also found that a sodium salt of the compound (IA) was
improved aqueous solubility significantly, and can be used as
active ingredient for injection in particular. In addition, the
inventors have found to be able to obtain the high purity of sodium
salt of the compound (IA) by using acid addition salt thereof.
[0009] The present invention provides the followings. [0010] (Item
1) An acid addition salt or a sodium salt of a compound represented
by the formula (IA):
##STR00003##
[0010] or a hydrate thereof; provided that the acid is 1) an acid
having a substituted or unsubstituted benzenesulfonic acid group or
2) a mixed acid comprising an acid having a substituted or
unsubstituted benzenesulfonic acid group and an inorganic acid.
[0011] (Item 2) The acid addition salt or its hydrate according to
Item 1. [0012] (Item 3) The acid addition salt or its hydrate
according to Item 1, wherein the salt is formed from acid selected
from 1) p-toluenesulfonic acid, 2) benzenesulfonic acid, or 3) a
combination p-toluenesulfonic acid or benzenesulfonic acid, and an
acid selected from sulfuric acid, hydrochloric acid and hydrobromic
acid. [0013] (Item 4) The acid addition salt or its hydrate
according to Item 1, wherein the salt is 1) p-tolueneslufonic acid
salt, or 3) the salt formed from the combination p-toluenesulfonic
acid and sulfuric acid. [0014] (Item 5) The acid addition salt or
its hydrate according to Item 4, comprising about 1.0 to about 2.0
mole equivalents of p-toluenesulfonic acid to the compound (IA).
[0015] (Item 6) The acid addition salt or its hydrate according to
Item 4, comprising about 1.0 to about 1.8 mole equivalents of
p-toluenesulfonic acid and about 0.1 to about 0.5 mole equivalents
of sulfuric acid to the compound (IA). [0016] (Item 7) The acid
addition salt or its hydrate according to any one of Items 1 to 6,
which is a crystalline solid. [0017] (Item 8) The acid addition
salt or its hydrate according to any one of Items 4 to 6, which is
a crystalline solid. [0018] (Item 9) The acid addition salt or its
hydrate according to Item 8, which is a single phase crystal or a
mixed crystal. [0019] (Item 10) The hydrate according to any one of
Items 4 to 9, wherein the content of water is about 12 to 17%.
[0020] (Item 11) The mixed crystal according to any one of Items 8
to 10, comprising a single phase crystal of 2 mole equivalents of
p-toluenesulfonic acid salt or its hydrate, and a single phase
crystal including 1 mole equivalent of p-toluenesulfonic acid salt
and 0.5 mole equivalents of sulfuric acid salt or its hydrate.
[0021] (Item 11-1) The crystalline solid of the hydrate of the acid
addition salt according to any one of Items 7 to 11, comprising 1.3
mole equivalents of p-toluenesulfonic acid and 0.5 mole equivalents
of sulfuric acid. [0022] (Item 12) The crystalline solid of the
hydrate according to any one of Items 7 to 11, which is a mixed
acid addition salt formed from 1.3 mole equivalents of
p-toluenesulfonic acid and 0.35 mole equivalents of sulfuric acid.
[0023] (Item 13) The crystalline solid of the hydrate of acid
addition salt according to any one of Items 7 to 12, comprising
about 20.2 to 23.2% of p-toluenesulfonic acid on an anhydrous basis
and, about 3.5 to 5.0% of sulfuric acid on an anhydrous basis.
[0024] (Item 14) The crystalline solid of the acid addition salt or
its hydrate according to any one of Items 8 to 13, wherein the
crystalline solid has at least three peaks of diffraction angles
(2.theta.) selected from: 8.2.degree..+-.0.2.degree.,
10.1.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree. and
20.3.degree..+-.0.2.degree. in an X-ray powder diffraction
spectrum. [0025] (Item 15) The crystalline solid according to any
one of Items 8 to 13, wherein the crystalline solid has at least
three peaks of diffraction angles (2.theta.) selected from:
8.2.degree..+-.0.2.degree., 8.9.degree..+-.0.2.degree.,
10.1.degree..+-.0.2.degree., 11.4.degree..+-.0.2.degree.,
13.0.degree..+-.0.2.degree., 19.9.degree..+-.0.2.degree.,
20.3.degree..+-.0.2.degree., 21.5.degree..+-.0.2.degree. and
26.2.degree..+-.0.2.degree. in an X-ray powder diffraction
spectrum. [0026] (Item 16) The crystalline solid according to any
one of Items 8 to 13, wherein the crystalline solid has at least
three peaks of diffraction angles (2.theta.) selected from:
8.2.degree..+-.0.2.degree., 8.9.degree..+-.0.2.degree.,
10.1.degree..+-.0.2.degree., 13.0.degree..+-.0.2.degree.,
16.5.degree..+-.0.2.degree., 17.1.degree..+-.0.2.degree.,
17.9.degree..+-.0.2.degree., 19.0.degree..+-.0.2.degree.,
20.3.degree..+-.0.2.degree. and 26.2.degree..+-.0.2.degree. in an
X-ray powder diffraction spectrum. [0027] (Item 17) A
pharmaceutical composition comprising the acid addition salt, its
hydrate or the crystalline solid thereof according to any one of
Items 1 to 16. [0028] (Item 18) A process for preparing the
crystalline solid of the acid addition salt or its hydrate
according to any one of Items 8 to 16, characterized by adding
p-toluenesulfonic acid and sulfuric acid to a solution containing
the compound (IA). [0029] (Item 19) The process for preparing the
crystalline solid according to Item 18, characterized by adding
about 2.2 to 2.5 wt % of p-toluenesulfonic acid monohydrate and
about 5 to 6 wt % of 75% sulfuric acid to the column eluate
containing the compound (IA). [0030] (Item 20) A sodium salt or its
hydrate according to Item 1. [0031] (Item 21) The sodium salt or
its hydrate according to Item 20, which is an amorphous. [0032]
(Item 22) A pharmaceutical composition comprising the sodium salt
or its hydrate according to Item 20 or 21. [0033] (Item 23) The
pharmaceutical composition according to Item 22, which is a
lyophilized formulation. [0034] (Item 24) A method for preparing a
lyophilized formulation comprising a sodium salt of the compound
(IA) or its hydrate, characterized by using the acid addition salt,
its hydrate or the crystalline solid thereof according to any one
of Items 1 to 16. [0035] (Item 25) A method for preparing a
lyophilized formulataion comprising a sodium salt of the compound
(IA) or its hydrate, characterized by freeze-drying a solution
containing the acid addition salt, its hydrate or the crystalline
solid thereof according to any one of Items 1 to 16 and sodium
hydrate. [0036] (Item 26) The method for preparing an acid addition
salt according to Item 24 or 25, wherein the acid addition salt is
formed from 1) p-toluenesulfonic acid, or 3) combination of
p-toluenesulfonic acid and sulfuric acid. [0037] (Item 27) A
pharmaceutical composition containing the compound (IA), its
pharmaceutically acceptable salt or a hydrate thereof, and further
sodium p-toluenesulfonate and/or sodium sulfate. [0038] (Item 28)
The pharmaceutical composition according to Item 27, containing a
sodium salt of the compound (IA) or its hydrate, and further sodium
p-toluenesulfonate and/or sodium sulfate. [0039] (Item 29) A
pharmaceutical composition comprising a sodium salt or an acid
addition salt of the compound (IA), its solvate, or a crystalline
solid thereof according to Item 1, for parenteral administration.
[0040] (Item 30) The pharmaceutical composition according to Item
29, for dermal, subcutaneous, intravenous, intraarterial,
intramuscular, intraperitoneal, transmucosal, inhalation,
transnasal, ophthalmic, inner ear, or vaginal administration.
[0041] (Item 31) The pharmaceutical composition according to any
one of Items 29 to 31, which is injection, infusion, eye drop, nose
drop, ear drop, aerosol, inhalation, lotion, impregnation,
liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch,
cataplasm, external powder or suppository. [0042] (Item 32) A
pharmaceutical composition comprising a sodium salt or an acid
addition salt of the compound (IA) or their solvate, or a
crystalline solid thereof according to Item 1, for pediatric or
geriatric patient.
Effects Of The Invention
[0043] The present invention provides an acid addition salt or a
sodium salt of the compound (IA), or a solvate thereof. In
particular, the acid addition salt is preferably provided that as a
crystalline solid.
The salts, its salvates or the crystalline solid thereof has at
least one of the following features: [0044] (1) good stability to
heat, humidity, solvates, light etc., high storage stability.
[0045] (2) good stability to coloration. [0046] (3) good solubility
in water or organic solvent. [0047] (4) a fast dissolution rate in
water or organic solvent. [0048] (5) high purity. [0049] (6) low
residual ratio of organic solvent. [0050] (7) excellent operation
for filtration, centrifugation, formulation etc. [0051] (8) small
specific volume. [0052] (9) it is difficult to charge. [0053] (10)
it is possible to be produced in high yield under low environmental
impact and be manufactured in volume. [0054] (11) it is useful as a
pharmaceutical active ingredient for an injection or a source
material for manufacturing them. [0055] (12) it is possible to be
adjusted in proper pH to inject into a vein without vascular pain,
therefore it has an advantage in control of fluid volume or
reduction excipients at the time of formulation. In particular, a
crystalline solid of the present invention has high stability under
the condition of the wide humidity range (e.g.: 25 to 99% RH) or
even in harsh environment (e.g.: high humidity).
BRIEF EXPLANATION OF THE DRAWINGS
[0056] Hereinafter, the type I crystal means a crystalline solid of
the hydrate of the mixed acid salt of the compound (IA), wherein
the mixed acid salt is formed from 1.3 mole equivalents of
p-toluenesulfonic acid and 0.35 mole equivalents of sulfuric
acid.
[0057] FIG. 1 shows an X-ray powder diffraction spectrum of the
crystalline solid of 8.5 hydrates of 2 mole equivalents
p-toluenesulfonic acid salt of the compound (IA) obtained in
Example 3. The horizontal axis represents a diffraction angle
2.theta.(.degree.), the vertical axis represents intensity
(Count).
[0058] FIG. 2 shows an X-ray powder diffraction spectrum of the
crystalline solid of the mixed acid salt of the compound (IA)
obtained in Example 4, wherein the mixed acid salt is formed from 1
mole equivalent of p-toluenesulfonic acid and 1 mole equivalent of
hydrochloric acid.
[0059] FIG. 3 shows an X-ray powder diffraction spectrum of the
crystalline solid of the mixed acid salt of the compound (IA)
obtained in Example 5, wherein the mixed acid salt is formed from 1
mole equivalent of p-toluenesulfonic acid and 1 mole equivalent of
hydrobromic acid.
[0060] FIG. 4 shows an X-ray powder diffraction spectrum of the
type I crystal D obtained in Example 6-1, wherein water content is
13.5%.+-.0.3%. FIG. 5 shows an X-ray powder diffraction spectrum of
the type I cystal E obtained in Example 6-2, wherein water content
is 13.8%.+-.0.3%.
[0061] FIG. 6 shows an X-ray powder diffraction spectrum of the
crystalline solid of 2 mole equivalents of bensenesulfonic acid
salt of the compound (IA) obtained in Example 7.
[0062] FIG. 7 shows a dynamic vapor sorption isotherm plot of the
type I crystal D conducted in Example 8.
[0063] FIG. 8 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 30% RH
in Example 8.
[0064] FIG. 9 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 40% RH
in Example 8.
[0065] FIG. 10 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 50% RH
in Example 8.
[0066] FIG. 11 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 60% RH
in Example 8.
[0067] FIG. 12 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 70% RH
in Example 8.
[0068] FIG. 13 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 80% RH
in Example 8.
[0069] FIG. 14 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 90% RH
in Example 8.
[0070] FIG. 15 shows an X-ray powder diffraction spectrum of the
type I crystal D, which was measured under the condition of 95% RH
in Example 8.
[0071] FIG. 16 shows an X-ray powder diffraction spectrum of the
crystalline solid of the hydrate of the mixed acid salt of the
compound (IA) obtained in Example 11, wherein the mixed acid salt
is formed from 1.05 mole equivalents of p-toluenesulfonic acid and
0.65 mole equivalents of sulfulic acid.
[0072] FIG. 17 shows an X-ray powder diffraction spectrum of the
crystalline solid of the hydrate of the mixed acid salt of the
compound (IA) obtained in Example 12, wherein the mixed acid salt
is formed from 1.0 mole equivalent of p-toluenesulfonic acid and
0.5 mole equivalents of sulfuric acid.
[0073] FIG. 18 shows an X-ray powder diffraction spectrum of the
crystalline solid of the hydrate of 2.0 mole equivalent of
p-toluenesulfonic acid salt of the compound (IA).
MODE FOR CARRYING OUT THE INVENTION
[0074] Herein, although the compound (IA) is represented by the
formula (IA):
##STR00004##
it can substantially go into the state of the formula (IA'):
##STR00005##
[0075] Therefore, the compound (IA) includes both structures. For
example, the sodium salt of the compound (IA) includes,
##STR00006##
[0076] Salt formation studies provide a means of altering the
phydicochemical and resultant biological characteristics of a drug
without modifying its chemical structure. A salt form can have a
dramatic influence on the properties of the drug. The selection of
a suitable salt is partially dictated by yield, rate and quantity
of the crystalline structure. In addition, hygroscopicity,
stability, solubility and the process profile of the salt form are
important considerations. Solubility of a salt form can affect its
suitability for use as a drug. Where aqueous solubility is low,
i.e. less than 10 mg/ml, the dissolution rate at in vivo
administration can be rate limiting in the absorption process
leading to poor bioavailability. Moreover, low solubility in water
can be limited choice of suitable administration routes since it is
difficult for administration by injection.
[0077] An acid to be used for forming an acid addition salts of the
compound (IA) includes one or two acids selected from acids having
a substituted or unsubstituted benzenesulfonic acid group and
inorganic acids (e.g.: sulfuric acid, hydrochloric acid, nitric
acid, hydrobromic acid, phosphoric acid, boric acid, etc.). In
particular, the acid having a substituted or unsubstituted
benzenesulfonic acid group is preferably p-toluenesulfonic acid,
benzenesulfonic acid, trifluoromethyl benzenesulfonic acid,
chlorobenzenesulfonic acid, methoxybenzenesulfonic acid or the
like, more preferably benzenesulfonic acid, p-toluenesulfonic acid
or the like. The inorganic acid is more preferably hydrochloric
acid, sulfuric acid or the like. Moreover the acid addition salt
may be selected from a mixed acid salt which is formed from a
combination of two or more acids selected from these acids, so a
mixed acid salt is preferably formed from a combination of an acid
having a substituted or unsubstituted benzenesulfonic acid group
and an inorganic acid. Particularly the mixed acid salt formed from
p-toluenesulfonic acid and hydrochloric acid, or the mixed acid
salt formed from p-toluenesulfonic acid sulfuric acid has high
stability to humidity etc. and excellent storage stability.
Although the acid addition salt is preferably crystalline solid, it
may be a single phase crystal or a mixed crystal.
[0078] A single phase crystal may be formed from a single kind of
acid addition salt or a mixed acid salt of two or more kinds of
acid. A mixed crystal is a crystalline solid, wherein two or more
kinds of single phase crystals are present as a mixture. For
example, a mixed crystal may be a mixture of a crystalline solid of
an acid addition salt, wherein the acid is an acid having
substituted or unsubstituted benzenesulfonic acid group, and a
crystalline solid of a mixed acid addition salt formed from a
combination of an acid having substituted or unsubstituted
benzenesulfonic acid group and an inorganic acid, or also be a
mixture of a crystalline solid of a mixed acid addition salt formed
form a combination of an acid having substituted or unsubstituted
benzenesulfonic acid group and an inorganic acid and the other
crystalline solid of a mixed acid salt formed from a combination of
an acid having substituted or unsubstituted benzenesulfonic acid
group and an inorganic acid, which is different from the above
combination.
[0079] The amount range of a mixed acid of an acid having
substituted or unsubstituted benzenesulfonic acid group and
inorganic acid to the compound (IA) is preferably an arbitrary
combination of about 1.0 to 1.9 mole equivalents of an acid having
a substituted or unsubstituted benzenesulfonic acid group and about
0.1 to 0.9 mole equivalents of an inorganic acid, more preferably
an arbitrary combination of about 1.0 to 1.5 mole equivalents of an
acid having substituted or unsubstituted benzenesulfonic acid group
and about 0.2 to 0.7 mole equivalents of an inorganic acid. Further
preferred amount range thereof is an arbitrary combination of about
1.2 to 1.4 mole equivalents of an acid having substituted or
unsubstituted benzenesulfonic acid group and about 0.3 to 0.7 mole
equivalents of an inorganic acid. The number of mole equivalents of
the acid may contain an acid as a residual solvent such as adhered
acid.
[0080] As embodiments of an acid addition salt of the present
invention or its solvate, preferably a crystalline solid,
p-toluenesulfonic acid salt (non-solvete) of the compound (IA),
hydrate of p-toluenesulfonic acid salt, a mixed acid salt formed
from p-toluenesulfonic acid and sulfuric acid (hereinafter,
p-toluenesulfonic acid-sufuric acid mixed acid salt) (non-solvate),
hydrate of p-toluenesulfonic acid-sulfuric acid salt, a mixed acid
salt formed from p-toluenesulfonic acid and hydrochloric acid
(hereinafter, p-toluenesulfonic acid-hydrochloric acid mixed acid
salt)(non-solvate), hydrate of p-toluenesulfonic acid-hydrochloric
acid mixed acid salt, a mixed acid salt formed from
p-toluenesulfonic acid and hydrobromic acid (hereinafter,
p-toluenesulfonic acid-hydrobromic acid mixed acid salt)
(non-solvate), hydrate of p-toluenesulfonic acid-hydrobromic acid
mixed acid salt, a mixed acid salt formed from p-toluenesulfonic
acid and nitric acid (hereinafter, p-toluenesulfonic acid-nitric
acid mixed acid salt) (non-solvate), hydrate of p-toluenesulfonic
acid-nitric acid mixed acid salt, a salt formed from
benzenesulfonic acid (non-solvate), hydrate of a salt formed from
benzenesulfonic acid and the like can be exemplified.
[0081] The kinds and content of the acid contained in the acid
addition salt of the present invention, its solvate, or crystalline
solid thereof includes, relative to the compound (IA), 1) about 1
to 2 mole equivalent of p-toluenesulfonic acid, 2) a mixed acid
comprising about 1.0 to 1.9 mole equivalents of p-toluenesulfonic
acid and about 0.1 to 0.9 mole equivalents of sulfuric acid, 3) a
mixed acid comprising about 1.0 to 1.9 mole equivalent of
p-toluenesulfonic acid and about 0.1 to 1.0 mole equivalents of
hydrochloric acid, 4) a mixed acid comprising about 1.0 to 1.9 mole
equivalents of p-toluenesulfonic acid and about 0.1 to 1.0 mole
equivalents of hydrobromic acid, 5) a mixed acid comprising about
1.0 to 1.9 mole equivalents of p-toluenesulfonic acid and about 0.1
to 1.0 mole equivalents of nitric acid, and 6) about 1 to 2 mole
equivalents of benzenesulfonic acid and the like. The number of
mole equivalents of the acid may contain an acid as a residual
solvent such as adhered acid, the number of mole equivalents of the
salvate may contain a residual solvent such as adhered solvent.
[0082] In particular, a preferred embodiment of a crystalline solid
of non-solvate or solvent of a mixed acid salt of the compound
(IA), wherein the mixed acid is formed from about 1.0 to 1.9 mole
equivalents of p-toluenesulfonic acid and about 0.1 to 0.9 mole
equivalents of sulfuric acid, is hydrate of a mixed acid salt
formed form an arbitrary combination of about 1.0 to 1.5 mole
equivalents of p-toluenesulfonic acid and about 0.2 to 0.6 mole
equivalents of sulfuric acid. More preferable is hydrate of a mixed
acid salt formed from an arbitrary combination of about 1.2 to 1.3
mole equivalents of p-toluenesolfonic acid and about 0.4 to 0.5
mole equivalents of sulfuric acid or, hydrate of a mixed acid salt
formed from an arbitrary combination of about 1.1 to 1.4 mole
equivalents of p-toluenesulfonic acid and about 0.3 to 0.7 mole
equivalents of sulfuric acid. Further preferable is hydrate of a
mixed acid salt formed from an arbitrary combination of about 1.3
mole equivalents and about 0.4 to 0.5 mole equivalents of sulfuric
acid. An another preferred embodiment is a mixed crystal of hydrate
of p-toluenesulfonic acid-sufuric acid mixed acid salt represented
by the above arbitrary combination, or a crystalline solid of
hydrate of a mixed acid salt formed from about 1 mole equivalent of
p-toluenesulfonic acid and about 0.5 mole equivalents of sulfuric
acid.
[0083] As the solvent for forming the solvates, water, ethanol,
2-propanol, methyl acetate, ethyl acetate, n-propyl acetate,
1,2-dimethoxyethane, methyl isobutyl ketone, acetonitrile or the
like is exemplified. Preferable is water, ethanol or 2-propanol.
More preferable is water. The preferred amount of the solvate is
about 0.5 to 20 mole equivalents, more preferable is about 5 to 17
mole equivalents. The water containing hydrate is preferably
crystal water, may be contained water as a residual solvent such as
adhered water.
[0084] The content of water of the present invention, for example,
can be selected from the range of about 5 to 20 wt %, may be about
10 to 20 wt %, or also about 10 to 20 wt %. Moreover the content of
water thereof, for example, can be selected from the range of about
0.5 to 20 mole equivalents, about 5 to 17 mole equivalents, or also
6 to 12 mole equivalents relative to the compound (IA). In
particular, the stabilities of a lot of the crystalline solid of
the present invention are improved dependent on increasing the
content of water thereof.
[0085] The acid addition salt or its solvate, preferably the
crystalline solid thereof is crystallized by stirring or leaving to
stand for several hours to several days while cooling to about -5
to 5.degree. C. as necessary after addition of generally about 0.5
to 50 mole equivalents of acid to the solution of the compound (IA)
by dropwise at about 0.degree. C. to room temperature. The
preferred amount of acid is about 5 to 40 mole equivalents, more
preferable is about 10 to 30 mole equivalents. The solvent is
preferably acetonitrile, acetone, water, ethanol, 2-propanol or a
two or more mixed solvent selected from them, more preferably
acetonitrile, water, or the mixed solvent thereof. The preparation
of the crystalline solid of the solvate is carried out by
dissolving the acid addition salt of the compound (IA) into a
solubilizing solvent containing the solvent to be solvated at least
at about 0.degree. C. to room temperature, and stirring or leaving
to stand the solution at about 0.degree. C. to room temperature for
several hours to three days. It can be collected from a solvent by
the ordinally separating mechanisms, such as filtration or
centrifugal separation, and isolated by the ordinary refining
means, such as washing and drying.
[0086] The "crystalline solid" used in this description means a
solid having a structure that atoms, ions, or molecules
constituting the solid are regularly alined, as it turned out that
a solid has periodicity or anisotropic nature. The "single phase
crystal" means a crystalline solid consisting of a single component
or a single structure. The "mixed crystal" means a mixture of two
or more kinds of single phase crystals, or a crystalline solid
constituting the periodic structure by two or more substances which
chemical components are different. "A crystalline solid
constituting the periodic structure by two or more substances which
chemical components are different" includes, for example, 1) a
crystalline solid crystallographically forms a homogeneous solid
phase, and it is a chemical mixture that ingredient substances are
mixed in various ratio (e.g.: solid solution consisting of a
non-metallic or a combination of metallic and non-metallic), 2) a
crystalline solid is constituted by two or more kinds of substances
on different chemical components, and a part of the periodic
structure thereof is substituted with another chemical component
substances, 3) a crystalline solid that the substrate atoms or
molecules penetrate into the gap of the periodic structure composed
of two or more kinds of substances on different chemical
components. Namely, "crystalline solid" includes "single phase
crystal" and "mixed crystal". Without a mention in particular, the
"crystal" is the same meaning as the "crystalline solid". The
degree of crystallinity of a crystalline form, for example, can be
measured by a number of techniques including an X-ray powder
diffraction measurement, a dynamic vapor sorption measurement,
differential scanning calorimetry, solution colorimetric
measuremet, dissolution profile etc.
[0087] The crystalline solid of the present invention may be a
single crystal, a twin crystal, a polycrystal and the like,
generally it is often a single crystal or a mixed crystals thereof.
A crystalline form (outline) is not particularly limited, for
example, it may be a triclinic crystal, a monoclinic crystal,
orthorhombus (orthorhombic crystal), tetragonal crystal, cubic
crystal, trigonal crystal (rhombohedron), hexagonal crystal or the
like, and also may be a spherulite, skeleton crystal, dendrite
crystal, needle crystal (e.g. crystal whisker) or the like. The
size of the crystal is not particularly limited, for example, the
average particle diameter of the crystal is 0.5 .mu.m to 1 mm,
preferably about 1 to 500 .mu.m based on a laser diffraction
method.
[0088] Moreover, a crystalline solid of an acid addition salt of
the compound (IA) or its solvate may come into being adsorption of
the moisture depending on a change in relative humidity, as it
turned out that its water of hydration may change. Namely, it may
be a crystalline solid that water molecules in air can easily move
in and out through its crystal lattice as crystal water depending
on the external humidity change. As regards such crystalline
solids, even when the X-ray powder diffraction pattern thereof have
been slightly changed along with the change of their water content,
these crystalline solid can be interpreted the substantial same
crystalline solid as long as they have characteristic peaks
described herein. The water may be either the crystal water or the
residual solvent such as adhered water. Further the crystalline
solid may be either a single phase crystal or a mixed crystal.
[0089] A crystalline solid of an acid addition salt of the compound
(IA) or its solvate is preferably characterized by diffraction
peaks in the X-ray powder diffraction spectrum.
[0090] The present invention also includes a mixed crystal composed
of a number of crystalline solids of the compound (IA) having
diffraction peaks at different diffraction angles mutually in an
X-ray powder diffraction spectrum. The mixed crystals include a
single phase crystal characterized by at least the following
diffraction peaks.
[0091] In the present specification, the diffraction peak may be a
single sharp peak (singlet type), one of gentle peak (broad form),
or about two to five of multiple peak (doublet type, triplet type,
quartet type, quintet type), and yet usually it is often one sharp
peak.
[0092] The crystalline solid of 8.5 hydrates of 2 mole equivalents
of p-toluenesulfonic acid salt of the compound (IA) shows an X-ray
powder diffraction pattern as shown in FIG. 1, and shows
characteristic peaks at diffraction angle (2.theta.):
8.1.+-.0.2.degree., 13.3.+-.0.2.degree., 17.4.+-.0.2.degree.,
19.1.+-.0.2.degree. and 21.3.+-.0.2.degree..
[0093] The crystalline solid of the mixed acid salt of the compound
(IA), wherein the mixed salt is formed from 1 mole equivalent of
p-toluenesulfonic acid and 1 mole equivalent of hydrochloric acid,
shows an X-ray powder diffraction pattern as shown in FIG. 2, and
shows characteristic peaks at diffraction angle (2.theta.):
8.5.+-.0.2.degree., 10.2.+-.0.2.degree., 20.3.+-.0.2.degree.,
24.6.+-.0.2.degree. and 26.2.+-.0.2.
[0094] The crystalline solid of the mixed acid salt of the compound
(IA), wherein the mixed salt is formed from 1 mole equivalent of
p-toluenesulfonic acid and 1 mole equivalent of hydrobromic acid,
shows an X-ray powder diffraction pattern as shown in FIG. 3, and
shows characteristic peaks at diffraction angle (2.theta.):
8.5.+-.0.2.degree., 10.3.+-.0.2.degree., 16.6.+-.0.2.degree.,
24.7.+-.0.2.degree. and 26.3.+-.0.2.degree..
[0095] The crystalline solid of 2 mole equivalents of
benzenesulfonic acid salt of the compound (IA) shows an X-ray
powder diffraction pattern as shown in FIG. 5, and shows
characteristic peaks at diffraction angle (2.theta.):
10.3.+-.0.2.degree., 13.3.+-.0.2.degree., 16.5.+-.0.2.degree.,
19.2.+-.0.2.degree. and 20.8.+-.0.2.degree..
[0096] The crystalline solid of the mixed acid salt of the compound
(IA), wherein the mixed acid is formed from 1.05 mole equivalents
of p-toluenesulfonic acid and 0.65 mole equivalents of sulfuric
acid, shows an X-ray powder diffraction pattern as shown in FIG.
16, and shows characteristic peaks at diffraction angle (2.theta.):
8.4.+-.0.2.degree., 10.2.+-.0.2.degree., 13.1.+-.0.2.degree. and
20.4.+-.0.2.degree..
[0097] The crystalline solid of the mixed acid salt of the compound
(IA), wherein the mixed acid is formed from 1.0 mole equivalent of
p-toluenesulfonic acid and 0.5 mole equivalents of sulfuric acid,
shows an X-ray powder diffraction pattern as shown in FIG. 17, and
shows characteristic peaks at diffraction angle (2.theta.):
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree.,
16.5.+-.0.2.degree. and 20.3.+-.0.2.degree..
[0098] The crystalline solid of hydrate of 2 mole equivalents
p-toluenesulfonic acid salt of the compound (IA) shows an X-ray
powder diffraction pattern as shown in FIG. 18, and shows
characteristic peaks at diffraction angle (2.theta.):
5.3.+-.0.2.degree., 8.0.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.0.+-.0.2.degree. and 20.3.+-.0.2.degree..
[0099] The type I crystal (:the crystalline solid of hydrate of the
mixed acid salt of the compound (IA), wherein the mixed acid is
formed from 1.3 mole equivalents of p-toluenesulfonic acid and 0.35
mole equivalents of sulfuric acid) shows an X-ray powder
diffraction pattern as shown in FIGS. 4, 5, or 7 to 15, shows
characteristic peaks at diffraction angle (2.theta.):
8.2.+-.0.2.degree., 8.9.+-.0.2.degree., 10.1.+-.0.2.degree.,
11.4.+-.0.2.degree., 13.0.+-.0.2.degree., 20.3.+-.0.2.degree. and
26.2.+-.0.2.degree.. In particular, diffraction angel (2.theta.):
8.2.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree. are more characteristic peaks.
[0100] A crystalline solid of an acid addition salt of the compound
(IA) or its solvate is preferably at least one peak selected from
diffraction angle (2.theta.): 8.2.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0101] A crystalline solid of an acid addition salt of the compound
(IA) or its solvate is preferably at least one peak selected from
diffraction angle (2.theta.): 8.2.+-.0.2.degree.,
8.9.+-.0.2.degree., 10.1.+-.0.2.degree., 11.4.+-.0.2.degree.,
13.0.+-.0.2.degree., 20.3.+-.0.2.degree. and
26.2.+-.0.2.degree..
[0102] A crystalline solid of an acid addition salt of the compound
(IA) or its solvate is preferably at least one peak selected from
diffraction angle (2.theta.): 8.2.+-.0.2.degree.,
8.9.+-.0.2.degree., 10.1.+-.0.2.degree., 11.4.+-.0.2.degree.,
13.0.+-.0.2.degree., 19.9.+-.0.2.degree., 20.3.+-.0.2.degree.,
21.5.+-.0.2.degree. and 26.2.+-.0.2.degree..
[0103] A crystalline solid of an acid addition salt of the compound
(IA) or its solvate is preferably at least one peak selected from
diffraction angle (2.theta.): 8.2.+-.0.2.degree.,
8.9.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree.,
16.5.+-.0.2.degree., 17.0.+-.0.2.degree., 17.9.+-.0.2.degree.,
19.0.+-.0.2.degree., 20.3.+-.0.2.degree. and
26.2.+-.0.2.degree..
[0104] The crystalline solid of the present invention is usually
prepared by crystallizing the compound (IA) in the oversaturated
state after dissolving the compound (IA) in the crystallization
solvent and/or acid. The crystallization method (the method for
making a transition to the oversaturated state) is not particularly
limited, for example, an evaporation method (a method for
evaporating the crystallization solvent from the crystallization
solution), a cooling method (a method for cooling the
crystallization solution or the solution of the compound (IA), an
antisolvent crystallization method (a method for adding an
antisolvent of the compound (IA) to the crystallization solution),
a seed crystal addition method (a method for adding a seed crystal
containing the compound (IA) to the crystallization solution) and
the like can be exemplified. For example, a crystalline solid of
the present invention can be manufactured by a seed crystal
addition method of crystallizing the compound (IA) by adding a seed
crystal to a solution dissolved the compound (IA) in the
crystallization solvent and/or the acid, after obtaining the seed
crystal from a evaporation method (a method of crystallization from
the crystallization solution in the oversaturated state obtained by
evaporating the crystallization solution (or the solution)
containing the compound (IA) and the crystallization solvent from
the crystallization solvent) or a cooling method (a method of
crystallization from the crystallization solution in the
oversaturated state obtained by cooling the crystallization
solution (or the solution) containing the compound (IA) and the
crystallization solvent)
According to this method, the crystalline solid can be manufactured
efficiently.
[0105] As a crystallization solvent, C.sub.1-4 alkanol such as
methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol
etc.; C.sub.5-6 alkane such as pentane, hexane etc.; di-C.sub.1-4
alkyl-ether such as diisopropylether; C.sub.2-4 ketone such as
acetone, methyl ethyl ketone; amide solvent such as
dimethylacetoamide, N-methylpyrrolidone etc.; acetonitrile, water
etc. can be exemplified. These crystallization solvent can be used
alone or as a mixed solvent.
[0106] The amount of the crystallization solvent, for example, is 1
to 100 mL, preferably 2 to 60 mL, and more preferably about 5 to 55
mL, for 1 g of the compound (IA).
[0107] Crystallization operation may be at once, and yet may be
repeated several times in order to improve the purity of the
crystalline solid. The crystallized material obtained by
crystallization is generally purified (separated from amorphous
material) by the separating means such as filtration and
centrifugal separation. The separated crystallized materials may be
dried.
[0108] The drying method may be any of natural drying, air-drying,
and drying under reduced pressure. For example, drying under
reduced pressure may be at about 1 to 100 hpa, preferably about 1
to 40 hpa (e.g. 1.5 to 10 hpa, 10 to 35 hpa). The drying
temperature, for example, may be room temperature to under heating,
preferably about 20 to 80.degree. C. The drying time, for example,
may be about 0.5 to 48 hours, preferably about 0.5 to 24 hours.
[0109] Additionally, a crystalline solid of an acid addition salt
of the present invention or its solvate can be synthesized by
adding an acid to the reaction solution or the solution such as a
column eluate containing the compound (IA). In detail, the
crystalline solid of an acid addition salt of the compound (IA) can
be obtained by adding about 2 to 40 wt % of the acid to the
reaction solution or a column eluate containing the compound (IA)
and adding the seed crystal as needed, and cooling to at about -5
to 5.degree. C., and then being stirred or leaving to stand for
about 1 hour to about 4 days to crystalize the compound (IA), and
being washed with cold water or the acid, and dried at normal
pressure or reduced-pressure for about 0.5 to 10 hours. Or, the
different crystalline solid of an acid addition salt from the
crystalline solid of the acid addition salt of the present
invention (for example, it is Z crystal) can be also obtained by
dissolving or suspending Z crystal in a crystallization solvent,
and performing salt exchange of the compound (IA) by adding a
different acid, and then crystallized from the resulting
solution.
[0110] For example, the crystalline solid of hydrate of 2 mole
equivalents of p-toluenesulfonic acid salt of the compound (IA) is
obtained as follows. Namely, to an acetonitrile solution, an
acetone solution, an aqueouos solution or a mixed solution thereof
containing the compound (IA) is added an aqueous solution of about
2 to 20 mole equivalents of p-toluenesulfonic acid to dissolve it,
and the resulting solution is crystallized by leaving to stand at
room temperature to about 0 to 5.degree. C. for about 1 to 4 days.
An obtained crystalline solid is washed with cold water and
air-dried at room temperature for about 1 to 3 hours to yield the
desired crystalline solid of hydrate of 2 mole equivalents of
p-toluenesulfonic acid salt.
[0111] Moreover, the type I crystal of the compound (IA) (: the
mixed crystal of hydrate of a mixed acid salt formed from 1.3 mole
equivalent of p-toluenesulfonic acid and 0.35 mole equivalents of
sulfuric acid) is obtained as follows. Namely, the crystalline
solid of hydrate of 2 mole equivalents of p-toluenesulfonic acid of
the compound (IA) is dissolved in a mixed solution of sulfuric acid
and water, and the resulting solution is crystallized by leaving to
stand at 0 to 5.degree. C. for about 1 to 4 days, the obtained
crystalline solid is washed with cold water and air-dried at room
temperature for about 0.5 to 2 hours to yield the type I crystal.
Or, to the mixed solution of acetonitrile and water containing the
compound (IA) is added sulfuric acid and a seed crystal as needed,
the resulting solution is colded to about -5 to 5.degree. C., and
stirred or leaving to stand for about 1 hour to about 4 days to
crystallize. The obtained crystalline solid is washed with cold
water or the acid and dried at normal pressure or reduced pressure
for about 0.5 to 10 hours to yield the type I crystal.
[0112] The type I crystal of the compound (IA) can include even
more about 0.01 to 0.1 mole equivalents of p-toluenesulfonic acid
and/or about 0.01 to 0.1 mole equivalents of sulfuric acid as
residual acid in some cases. The residual acid may sometimes be
contained in a form to be adhered to the crystal or incorporated
into the crystal.
[0113] Further, a crystalline solid of an acid addition salt of the
present invention can be synthesized by salt exchange from an acid
addition salt crystal of different composition. For example, the
crystalline solid of hydrate of 2 mole equivalents of
p-toluenesulfonic acid salt of the compound (IA) is dissolved or
suspended in the crystallization solvent and/or the acid, and added
the corresponding acid and cooled to about -5 to 5.degree. C. The
resulting solution is crystallized while performing salt exchange
by stirring or leaving to stand for about 1 hour to about 4 days.
The obtained crystalline solid is washed with cold water or the
acid, and dried at normal pressure or reduced pressure for about
0.5 to 10 hours to be able to yield a crystalline solid of an acid
addition salt of the present invention.
[0114] As the preferred amount of acid in the manufacturing method
of the type I crystal of the compound (IA) (: a mixed crystal of
hydrate of a mixed acid salt formed from 1.3 mole equivalents of
p-toluenesulfonic acid and 0.35 mole equivalents of sulfuric acid),
p-toluenesulfonic acid monohydrate is about 2 to 3 wt %, more
preferably about 2.2 to 2.5 wt % of p-toluenesulfonic acid
monohydrate for the solution containing the compound (IA), and
sulfuric acid is about 4.5 to 7 wt %, more preferably about 5 to 6
wt % for the solution containing the compound (IA). Or, for 1
ptswt. of the compound (IA), p-toluenesulfonic acid monohydrate is
about 1.2 to 1.5 ptswt., and 75% sulfuric acid is about 2.7 to 3.5
ptswt.
[0115] Specifying methods of the crystalline solid of the present
invention are illustrated below.
If there is no reference in particular, the numerical value of the
description and claims is a near value. A numerical change
originates in a device calibration, a device error, the purity of a
substance, a crystal size, a sample size, and the other
factors.
[0116] The crystalline solid of the present invention is clearly
identified by spectrophotometrical probes (e.g. an X-ray
diffraction, an infrared spectrum, a Raman sprctrum, and solid
NMR).
[0117] The crystalline solid of the compound (IA), its acid
addition salt, or a solvate thereof is preferably identified by an
X-ray powder diffraction profile. The characteristic diffraction
peaks are selected from preferably about 10, more preferably about
5, further preferably about 3 in a diffraction patterns.
[0118] Scince an error in the range of .+-.0.2.degree. may occur in
diffraction angles (2.theta.) in X-ray powder diffraction, in
general, the value of the above diffraction angle should be
understood as including value in a range of around .+-.0.2.degree..
Therefore, the present invention includes not only the crystalline
solids whose diffraction angles of the peaks in X-ray powder
diffraction perfectly match, but also crystals whose diffraction
angles of the peaks match within an error of around
.+-.0.2.degree..
[0119] In general, it is known that the relative intensities and
absolute intensities of various peaks shown in the Tables and
Figures below may vary to a number of factors such as orientation
effects of crystalline solids in the X-ray beam, influence of
coarse particles, the purity of the material being analyzed, or the
degree of crystallinity of the sample. The peak position may also
shift for variations in sample height. Furthermore, measurements
using a different wavelength will result in different shifts
according to the Bragg equation (n.lamda.=2d sin .theta.). Such
further XRPD patterns obtained by using a different wavelength are
within the scope of the present invention.
[0120] The characteristic diffraction peaks as used herein are
peaks selected from the observed diffraction pattern. In order to
distinguish between multiple crystalline solid, a peak which is
shown for the crystal and not shown for the other crystalline solid
becomes a more preferable characteristic peak than the size of a
peak when the crystalline solid is specified. The crystalline solid
can be characterized by one or two peak(s) if it is such
characteristic peak(s).
[0121] In particular the type I crystal can be distinguished from
the other crystalline forms (e.g., anhydrous etc.) disclosed herein
by the presence of characteristic diffraction peaks. Further, by
comparing the chart obtained by measuring, if these characteristic
peaks coincicide, the X-ray powder diffraction spectrum can be said
to substantially match up. The water content of the type I crystal
can be changed by the relative humidity, and the hydration state
thereof can be changed. The type I crystals having such as the
different water content have the characteristic peaks in common as
shown in FIGS. 4, 5 or 8 to 15.
[0122] The characteristic peaks in common are at least three peaks
selected from diffraction angle (2.theta.): 8.2.+-.0.2.degree.,
8.9.+-.0.2.degree., 10.1.+-.0.2.degree., 11.4.+-.0.2.degree.,
13.0.+-.0.2.degree., 19.9.+-.0.2.degree., 20.3.+-.0.2.degree. and
26.2.+-.0.2.degree.. The more preferable characteristic peaks in
common are at least three peaks selected from diffraction angle
(2.theta.): 8.2.+-.0.2.degree., 10.1.+-.0.2.degree.,
13.0.+-.0.2.degree. and 20.3.+-.0.2.degree..
[0123] Single crystal structure analysis (See Toshio Sakurai et al.
"A guidance of X-ray structural analysis" Shokabo issue (1983),
Stout & Jensen et al. X-Ray Structure Determination: A
Practical Guide, Macmillan CO., New York (1968)) is one method of
identifying a crystal, it is possible to obtain a crystallographic
parameters of the crystal, futher an atom coordinate (value showing
the spatial positional relation of each atoms) and a three
dimensions structural model. Single crystal structure analysis is
useful for identifying the structure of crystals of a complex such
as the present invention.
[0124] Infrared absorption spectroscopy is a methods to determine
the degree of absorption of infrared when it goes through samples
with each wavenumber. Infrared absorption spectrum is usually shown
in a graph of wavenumber on the horizontal axis and transmittance
or absorbance on the vertical axis. The wavenumber and
transmittance (or absorbance) of an absorption peak may be readable
from the graph, or a calculated value by a data processing
equipment can be used. The infrared absorption spectrum is
determined by a chemical structure of the substance. Therefore, the
substance may be determined and fixed quantity by measuring
absorption of various wavenumbers. Crystal polymorphs can be
distinguished by comparing the absorption bands of the
characteristic functional groups for the crystal polymorph, that
is, mainly the functional groups related to a hydrogen bond in the
crystal structure such as C.dbd.O bond, OH bond, NH bond and the
like, and the other characteristic functional groups such as C--X
(halogen), C.dbd.C, C.ident.C and the like. The absorption bands
for characteristic functional group are selected form about 20,
more preferably about 10, the most preferably about 5 absorption
peaks. Usually, the absorption spectrum of a sample is measured in
a range of 4000 cm.sup.-1 to 400 cm.sup.-1 of wavenumber. Infrared
absorption spectroscopy is carried out under the same operation
conditions in which resolution of device, and scale and accurancy
of wavenumber are confirmed.
[0125] Scince an error in the range of .+-.2 cm.sup.-1 may occur in
absorption bands (cm.sup.-1) in infrared absorption spectroscopy,
in general, the value of the above absorption peaks should be
understood as including values in a range of around .+-.2
cm.sup.-1. Therefore, the present invention includes not only
crystals whose absorption peaks in infrared absorption spectroscopy
perfectly match, but also crystals whose absorption peaks match
within an error of around .+-.2 cm.sup.-1.
[0126] Infrared abdorption spectroscopy includes a measurement
method for potassium bromide tablets, solution, paste, liquid
membrane, thin film or gas samples, ATR method, diffuse reflection
method and the like. Among them, ATR method (Attenuated total
reflection) is called as a total reflection measurement method and
one of the reflection methods. This is a method that a sample is
adhered to surface of prism made from a substance with high
refractive index such as KRS-5, light is entered in a prism at an
optimal angle or more, and fully-reflected light is measured on the
border of prism and sample to obtain the absorption spectrum.
Because one of the conditions to measure by the ATR method is that
the refractive index of prism is larger than that of the sample, it
is necessary to change material of prism depending on the sample.
Additionally, the other condition is that the prism and sample must
be adhered. Therefore, the ATR method is suitable to measure
liquid, powder, plastic, soft rubber or the like, and has advantage
to be able to measure without chemical or physical treatment of a
sample. On the other hand, a diffuse reflection method is a method
to measure as powder without making a potassium bromide tablet in
measurement for powder samples. When a sample is exposed to light,
light which regularly reflect on surface of powder and goes outside
and diffuse reflection light (scattering light) which enters inside
of the sample, repeats transmission and diffusion, and then go on
the surface are occurred. The latter is used for the diffuse
reflection method to obtain an absorption spectrum.
[0127] Raman spectrum is shown characters of molecular or lattice
vibrations. The origin is a non-resistance collision of a molecular
and a photon which is light particle including light ray. The
collision of the molecular and photon brings exchange of energy. As
a result, energy and then wavelength of the photon change. That is,
Raman spectrum is a set of lines in extremely narrow spectrum
emitted from the target molecule when it is exposed to the incident
light. Width of each spectrum line is largely affected by spectrum
width of the incident light and then light source strictly in one
color, for example, laser is used. Wavelength of each Raman line is
shown by wavenumber shift from the incident light and it is
difference between the recioricals of wavelengths of Raman line and
incident light. Raman spectrum is to measure vibration state of
molecular and determined by the molecular structure.
[0128] Scince an error in the range of .+-.2 cm.sup.-1 may occur in
absorption bands (cm.sup.-1) in Raman spectrum, in general, the
value of the above absorption peaks should be understood as
including values in a range of around .+-.2 cm.sup.-1. Therefore,
the present invention includes not only crystals whose absorption
peaks in Raman spectrum perfectly match, but also crystals whose
absorption peaks match within an error of around .+-.2
cm.sup.-1.
[0129] Solid state .sup.13C-NMR (Nuclear magnetic resonance) is
useful to identify a crystal form because (i) the number of spectra
corresponds to carbon number of the compound, (ii) range of
chemical shift is wide compared with .sup.1H-NMR, (iii) signals are
sharp compared with Solid state .sup.1H-NMR, (iv) chemical shift
does not change even if an additive is include, or the like. It is
expected that the observed chemical shifts slightly change
according to a used specific spectrometer or a sample preparation
technique of an analyst. The error span in a solid state
.sup.13C-NMR spectrum is approximately .+-.0.5ppm.
[0130] The crystalline solid of the present invention cay be
identified by methods of the thermal analysis.
[0131] DSC (differential scanning calorimetry), one of the main
measuring methods for thermal analysis, is a method of measuring
the thermal properties of the substance as an aggregate of an
atom(s) and a molecule(s). A differential scanning calorimetry
curve can be obtained by measuring temperatures or change of heat
capacity over tie of a pharmaceutical active ingredient by DSC, and
plotting the obtained data to temperatures or times. From a
differential scanning calorimetry curve, the information about the
onset temperature, melting endothermic maximum and enthalpy of a
pharmaceutical active ingredient can be obtained.
[0132] As to DSC, it is known that the observed temperature can
depend on rate of temperature change, the sample preparations
techniques or the specific devices. Thus, "melting point" in the
DSC refers to the onset temperature less affected of the sample
preparation techniques. The error span in the onset temperature
obtained from a differential scanning calorimetry curve is
approximately .+-.2.degree. C.
[0133] TG/DTA (Thermogravimeric/Differential Thermal Analysis) is
one of the major measuring methods of a thermal analysis, and is
the method of measuring the weight and the thermal property of a
substance as an aggregate of an atom and a molecule. TG/DTA is the
method of measuring change of the weight and the quantity of heat
concerning the temperature or time of an active pharmaceutical
ingredient, and TG (thermo gravity) and a DTA (Differential Thermal
Analysis) curve are obtained by plotting the obtained data to
temperature or time. From TG/DTA curve, the information on the
weight about decomposition of an active pharmaceutical ingredient,
dehydration, oxidation, reduction, sublimation, and evaporation and
quantity-of-heat change can be acquired.
[0134] It is known that the temperature and the weight change
observed can be dependent on heating rate, the sample preparation
technique to be used, and a specific device about TG/DTA. In
authorization of the identity of crystal, an overall pattern is
important and may change with measurement conditions to some
degree.
[0135] Dynamic vapor sorption (DVS) is a gravimetric technique that
measures how quickly and how much of water is absorbed and desorbed
by a sample in several relative humidity (RH).
[0136] A degree of water absorption is calculated by weight change
in controlled humidity increased from 0% RH to 95% RH stepped 5% or
10%. Similarly, a degree of water desorption is calculated in
humidity decreased from 95% RH to 0% RH.
[0137] An absorption-desorption isotherm is obtained by plotting a
value of weight change in each humidity. These results can provide
the information of adhered water absorption and desorption. When
the anhydrate crystal transforms to hydrate crystal by humidity,
the results of measurement indicate transformation humidity and
amount of crystal water.
[0138] The results of absorption and desorption behavior of adhere
water or crystal water are affected by particle diameter,
crystallinity and crystal habit.
[0139] The sodium salt of the compound (IA) or a solvate thereof is
obtained by adding a sodium source such as sodium hydroxide or
sodium bicarbonate to the solution containing the compound (IA) to
adjust the pH to about 5 to 6.5, and then concentrating under
reduced pressure and/or lyophilizing. The sodium salt or a solvate
thereof has the advantageous characteristics such as: 1) high
solubility in water, 2) good stability against heat, moisture,
dissolution and/or light, 3) small specific volume, 4) difficult
charged, 5) it can be manufactured in a low environment burden
condition, 6) it can be mass produced, 7) it can be controlled to a
suitable pH range to administer into a vein without vascular pain,
8) it has a suitable property for lyophilized formulation, or 9)
fast dissolution rate in water, and the like.
[0140] The sodium salt of the compound (IA) is useful as
pharmaceutical active ingredient or its raw material. Although the
sodium salt can be produced from the compound (IA) directly, it can
be also obtained by lyophilizing a aqueous solution containing the
acid addition salt of the compound (IA) or a solvate thereof,
preferably a crystalline solid thereof and sodium hydroxide and
optionally other additives (e.g. sugars, pH modifiers, sodium
chloride or magnesium chloride) in accordance with techniques well
known in the art. The sodium salt of the compound (IA) is
preferably non-crystalline, that is an amorphous form, and its
water solubility is very high.
[0141] As the condition for lyophilizing, a condition for freezing
is at about -50 to -3.degree. C. for 0.5 to 5 hours, preferably
about -40 to -5.degree. C. for 1 to 4 hours, and a condition for
annealing is about -40 to -20.degree. C. for 1 to 3 hours,
preferably about -35 to -25.degree. C. for 1.5 to 2.5 hours, a
condition of primary drying is at about -50 to -10.degree. C. for
0.1 to 150 hours at about 5 to 20 Pa in vacuum pressure, preferably
at about -40 to -20.degree. C. for 0.5 to 130 hours, at 7.5 to 15
Pa in vacuum pressure, and a condition of secondary drying is at
about 15 to 70.degree. C. for 1 to 7 hours at 5 to 20 Pa in vacuum
pressure, preferably at about 20 to 65.degree. C. for 1.5 to 6.5
hours at 5 to 20 Pa in vacuum pressure.
[0142] The formulation of the present invention after lyophilizing
is administered after adding a solution such as a distilled water
for injection, normal saline solution or glucose solution at the
time of use to dissolve. The pharmaceutical composition of the
present invention exhibits a strong antibacterial spectrum against
Gram-positive bacteria and Gram-negative bacteria, especially
.beta.-lactamase producing Gram-negative bacteria, and it does not
exhibit cross-resistance with existing cephem drugs and
carbapenems.
[0143] The compound (IA) of the present invention, its sodium salt,
its acid addition salt, or or a solvate thereof has a broad
antibacterial spectrum, especially it has strong antibacterial
activity against .beta.-lactamase producing Gram-negative bacteria
(e.g.: Class B type of metallo-.beta.-lactamase producing
Gram-negative bacteria). Thus, it is effective for prevention or
therapy against a variety of diseases caused by causative bacteria
in a variety of mammals including humans, for example, airway
infectious diseases, urinary system infectious diseases,
resipiratory system infectious diseases, sepsis, nephritis,
cholecystitis, oral cavity infectious diseases, endocarditis,
pneumonia, bone marrow membrane myelitis, otitis media, enteritis,
empyema, wound infectious diseases, opportunistic infection and the
like.
[0144] Scince the salt of the present invention or its solvate, and
a crystalline solid thereof has high solubility, it is particularly
suitable as an injection. Moreover, the salt of the present
invention or its solvate, and a crystalline solid thereof also has
advantages as pharmacokinetics of high blood concentration, long
duration of effect and/or remarkable tissue migration and the like.
Furthermore, the salt of the present invention or its solvate and a
crystalline solid thereof has high stability in human plasma, and
is extremely effective as a medicine. Additionally, scince the salt
of the present invention or its solvate and a crystalline solid has
advantagenous characteristics in manufacturing sides such as: (1)
good stability against heat, moisture, dissolution and/or light,
(2) its storage stability and/or coloring stability is good, (3) it
is possible to provide a high purity drug substance, (4) easy
operation of filtration or cntrifugation, (5) it improves the
solvent removal efficiency, (6) small specific volume, (7) it is
difficult to charge, (8) it can be manufactured in a low
environment burden condition, (9) it can be mass produced, and the
like, it is usuful as a source material for manufacturing
medicine.
[0145] The salt of the present invention or its solvate and a
crystalline solid thereof can be administered to a patient directly
or a pharmaceutical composition in which the crystalline solid
described above is blended with a pharmaceutical carrier or
excipient can also be administered. The technical information for
the formulation and administration of the drug can be found out to
"Remington's Pharmacological Sciences" Mack Publishing Co., Easton,
Pa. the latest version.
[0146] A pharmaceutical composition of the present invention can be
administered orally or parenterally. Methods for parenteral
administration include dermal, subcutaneouos, intravenous,
intraarterial, intramuscular, intraperitoneal, transmucosal,
inhalation, transnasal, ophthalmic, inner ear or vaginal
administration and the like.
[0147] In case of oral administration, any forms, which are usually
used, such as oral solid formulations (e.g., tablets, powders,
granules, capsules, pills, films or the like), oral liquid
formulations (e.g., suspension, emulsion, elixir, syrup, lemonade,
spirit, aromatic water, extract, decoction, tincture or the like)
and the like may be prepared according to the usual method and
administered. Wherein the tablets can be sugar-coated tablets,
film-coated tablets, enteric-coating tablets, sustained-release
tablets, troche tablets, sublingual tablets, buccal tablets,
chewable tablets or orally disintegrated tablets. Powders and
granules can be dry syrups. Capsules can be soft capsules, micro
capsules or sustained-release capsules.
[0148] In case of parenteral administration, any forms, which are
usually used, such as injection (e.g., intravenous injection,
intramuscular injection, intraveneous drip, ampule for subcutaneous
injection, vials, solutions, suspensions or the like), local
administration agent (e.g., ear drops, nasal drops, eye drops,
ointmetns, emulsions, sprays, aerosols, inhalants, suppositories,
or the like), external preparations (e.g., lotions, injection
agents, coating agents, mousewashs, enemas, ointments, plasters,
jellies, creams, patches, cataplasms, external powders,
suppositories or the like) and the like can be preferably
administrated. Wherein injections can be emulsions whose type is
O/W, W/O, O/W/O, W/O/W or the like. In particular, injections can
be prepared by using a powder-filled formulation or a lyophilized
formulation containing the salt of the present invention or its
solvate, or a crystalline solid thereof. Preferably, it is a
lyophilized formulation containing the salt of the present
invention or its solvate or a crystalline solid thereof. The
lyophilized formulation of the present invention can be used as an
aqueous solution for application such as injection. In this case,
the salt or the crystalline solid having good solubility in water
or good dissolution rate in water is preferable. Preferably, it is
the sodium salt of the compound (IA).
[0149] The pharmaceutical composition may be manufactured by mixing
an effective amount of the compound of the present invention with
various pharmaceutical additives suitable for the formulation, such
as excipients, binders, disintegrants, lubricants, and the like.
Furthermore, the pharmaceutical composition can be for pediatric
patients, geriatric patients, serious cases or operations by
appropriately changing the effective amount of the compound of the
present invention, formulation and/or various pharmaceutical
additives. The pediatric pharmaceutical compositions are preferably
administered to patients under 12 or 15 years old. In addition, the
pediatric pharmaceutical compositions can be administered to
patients who are under 27 days old after the birth, 28 days to 23
months old after the birth, 2 to 11 years old, 12 to 16 years old,
or 18 years old. The geriatric pharmaceutical compositions are
preferably administered to patients who are 65 years old or
over.
[0150] Although a suitable route for administration is not limited,
it is possible to include oral, intrarectal, transmucosa, enteral,
intramuscular, subcutaneous, intraspinal, intrathecal, direct
intraventricular, intravenous, intraperitoneal, intranosal,
intraocular administration, and injection. Intravenous injection is
preferable. The pharmaceutical composition of the present invention
can be prepared by a method well known in the technical field such
as a conventional mixing, dissolution, granulation, sugar-coating,
powderization, emulsifying, encapsulation, packing and
lyophilization processes.
[0151] The pharmaceutical composition used in the present invention
can be formulated by a known method using one or more of
pharmaceutically acceptable carrier including an excipient and an
additive which make easy to prepare pharmaceutically allowable
formulation comprising the crystal of the present invention. A
suitable formulation depends on a selected route of administration.
The above formulation may contain appropriate additives: for
example, excipients, auxiliaries, stabilizers, wearing agents,
emulsifirs, the other additives depending on the dosage form. It is
necessary that these additives are available pharmaceutically and
pharmacologically, and they do not have an effect on the
cephalosporin derivatives. For example, the formulations for oral
include lactose, stearic acid, magnesium stearate, terra alba,
sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil,
olive oil, cacao butter, ethylene glycol, tartaric acid, citric
acid, fumaric acid or the like. The formulations for parenteral may
include solvent (alcohol, buffer, methyl oleate, water etc.),
buffering agents, dispersing agents, solubilizing agents,
stabilizing agents (methyl p-hydroxybenzoate or ethyl
p-hydroxybenzoate, sorbic acid etc.), absorption enhancers (mono-
or di-octanoate esters etc.), anti-oxidants, fragrances, analgesic
agents, suspending agents, side effect inhibitor, action-enhancing
substances (absorption excretion modifiers, anti-enzymatic
degradation agents, .beta.-lactamase inhibitors, other types
antimicrobial agents etc.).
[0152] Besides the above additives, anti-oxidant, buffers, soothing
agents and preserving agents can be added to the salt of the
present invention or its solvate or a crystalline solid thereof,
whose additives can be stabilized them and be used for injection
and are described in Japanese Pharmacopoeia, the Japanese
Pharmaceutical Codex, the Pharmaceutical Additives Standards and
Food Additives Compendial. Specifically, as an antioxidant, sodium
bisulfite, sodium pyrosulfite, ascorbic acid and the like are
included. As a buffers, citrate, acetate, phosphate and the like
are included. As a soothing agent, procaine hydrochloride,
lidocaine hydrochloride, chlorobutanol, benzyl alcohol and the like
are included. As a preservatibe, methyl parahydroxybenzoate, propyl
parahydroxybenzoate, ohenol, cresol, benzyl alcohol, chlorobutanol,
chlorocresol and the like are included.
[0153] When administering by injection, the salt of the present
invention or its solvate, or a cystalline solid thereof can be
administered after dissolving it in an aqueous solution,
preferably, in Ringer's solution or a buffer solution such as
physiological saline, which are physiologically acceptable.
Moreover, bases for pH adjustment (e.g., sodium hydroxide etc.) and
the like may be used. In a case of transmucosal administration, it
can be achieved by using a penetrating agent suitable for the
target barrier. The penetrating agent conventionally used in the
technical field can be used. As a carrier in a case of use as
capsules, granules, tablets, publicly known excipients (e.g.,
starch, lactose, sucrose, calcium carbonate, calcium phosphate
etc.), binders (e.g., starch, gum arabic, carboxymethyl cellulose,
hydroxypropyl cellulose, crystalline cellulose etc.), lubricants
(e.g., magnesium stearate, talc etc.) and the like are
included.
[0154] The pharmaceutical composition containing the salt of the
present invention or its solvate or a crystalline solid thereof can
also include appropriate solids or carrirs of gel phase or
excipients. As these carrirs or excipients, for example, inorganic
salt (e.g., sodium chloride, magnesium chloride, calcium carbonate,
calcium phosphate etc.), organic salts (e.g., sodium
p-toluenesulfonate, sodium gluconate, sodium citrate etc.), sugar
or sugar alcohols (e.g., glucose, fructose, sucrose, trehalose,
mannitol etc.), acid (e.g., gluconic acid, citric acid etc.),
polymers (e.g., starch, cellulose derivatives, gelatin,
polyethylene glycol etc.) and the like are exemplified. One or more
salt(s) selected from inorganic salts and organic salts and sugar
or sugar alcohols are preferable.
[0155] Although a pharmaceutical composition containing a salt of
the present invention or its solvate or a crystalline solid thereof
is obtained by drying after dissolving or suspending the salt of
the present invention or its solvate, or a crystalline solid
thereof and additives to water, the drying methods should be a
drying method that the salt of the present invention or its solvate
or a crystalline solid thereof is stable. Specifically, although
the suction drying method using an evaporator, spray drying method,
freeze-dried method and the like are exemplified, preferably is
freeze-drying method. The desirable pharmaceutical composition of
the present invention is freeze-dried product.
[0156] As a specific method for manufacturing a pharmaceutical
composition containing a salt of the present invention or its
solvate or a crystalline solid thereof, [0157] 1) a salt of the
present invention or its solvate or a crystalline solid thereof is
put in water for injection to prepare a acidic slurry liquid,
[0158] 2) to a slurry liquid of 1) is added sodium hydroxide
aqueous solution to adjust to pH 5.5 to 6, and then additives are
added, [0159] 3) water for injection is added to them to adjust
their concentration to 5 w/w %, a formulation solution is prepared
by sterile filtered the resulting solution, [0160] 4) a quantity of
the preparation solution of 3) is dispensed in vials or ampoules or
the like and lyophilized them to manufacture the desired
pharmaceutical composition. The vacuum freeze dryer can be used as
a freeze dryer.
[0161] Although it is desirable to set the dose of the salt of the
present invention or its solvate or a crystallinesolid thereof in
consideration of the age of the patient, body weight, disease type
and degree or administration route and the like, the dose in a case
of orally administration is usually 1 .mu.g to 1 g/day, preferably
is 0.01 to 200 mg/day, the dose in a case of parenteral
administration is usually 1 .mu.g to 10 g/day, preferably 0.1 mg to
10 mg/day. It may be administered once to several times in a
day.
EXAMPLES
[0162] The present invention is explained in more detail by
examples below, but these examples do not limit the present
invention. Although an effort to guarantee accuracy about numerical
values (for example, quantity, temperature, etc.) is paid, some
errors and deviations should be taken into consideration. If not
shown in particular, % is weight % of a component, and weight % is
weight % of the full weight of a composition, and equivalent is
mole equivalent of a component. A pressure is an atmospheric
pressure or a pressure near it. A definition of abbreviations used
in the present description is as follows: g is a gram, L is a
liter, mg is a milligram, mL is a milliliter, and EDC is
1-ethyl-3-(3-dimethylamino propyl) carbodiimido.
(Measurement of an X-Ray Powder Diffraction Pattern)
[0163] X-ray powder diffraction measurement of the crystalline
solid obtained in each example was performed on any one of the
following measurement condition 1 to 3 in accordance with the X-ray
powder diffraction method described to General Test Procedures of
the Japanese pharmacopoeia. It should be noted that the aluminium
plate is used as a sample folder. The peak whose 2-theta (2.theta.)
value is around 38.degree. is the peak of aluminium.
Measurement Condition 1:
(Device)
[0164] D-8 Discover (Bruker)
(Operation Method)
[0164] [0165] Measuring method: Reflection method [0166] The kind
of light source: Cu bulb [0167] Operation wavelength: CuK .alpha.
rays [0168] Tube current: 40 mA [0169] Tube voltage: 40 Kv [0170]
Sample plate: Al [0171] Sample range: 3.degree.-40.degree. [0172]
Exposure time: 120 s
Measurement Condition 2:
(Device)
[0172] [0173] TINT TTR III (Rigaku)
(Operation Method)
[0173] [0174] As to each sample, the following measurement
condition was adopted. [0175] Measuring method: Reflection method,
parallel method [0176] The kind of light source: Cu bulb [0177]
Operation wavelength: CuK .alpha. rays [0178] Tube current: 300 mA
[0179] Tube voltage: 50 Kv [0180] The angle of incidence of the
X-ray (2.theta.): 4.degree. to 40.degree. [0181] Sampling width:
0.02.degree. [0182] Scan speed: 5.degree./min
Measurement Condition 3:
(Device)
[0182] [0183] RINT2100 Ultima+ (Rigaku Corp.)
(Operation Method)
[0183] [0184] Measuring method: Reflection method [0185] The kind
of light source: Cu bulb [0186] Operation wavelength: CuK .alpha.
rays [0187] Tube current: 40 mA [0188] Tube voltage: 40 Kv [0189]
Sample plate: Al [0190] Sample range: 5.degree. to 35.degree.
[0191] Sampling width: 0.020.degree. [0192] Scan speed:
30.degree./min
(Measurement of TG/DTA Data)
[0193] About 5 mg of each crystalline solid obtained in each
example were measured, and an aluminium pan was stuffed with it and
measured in the open system.
(Measurement Conditions)
[0194] Device: TG/DTA 6300 by SEIKO [0195] Measurement temperature
range: 25.degree. C.-300.degree. [0196] Heating rate: 10.degree.
C./min
(Measurement of Solid State .sup.13C-NMR Spectrum)
[0197] The solid state .sup.13C-NMR spectrum of the crystalline
solid obtained in each example can be measured by the following
conditions using Varian 600MHz NMR Systems. [0198] Spectral width:
43103.4 Hz [0199] Acquisition Time: 0.04 s [0200] Sequence: tancpx
[0201] Recycle Delay: 10 s [0202] Contact Time: 3 ms [0203]
External standard: adamantane (38.52 ppm) or glycine (43.67 ppm)
[0204] Measurement temperature: 10.degree. C. [0205] Rotation
speed: 20000 rps [0206] Probe: 3.2 mm T3 HX Probe
(Measurement of Dynamic Vapor Sorption)
[0207] The dynamic vapor sorption measurement of the crystalline
solid obtained in each example was carried out. The sample of about
18.0 mg was measured and transferred to a sample pan, and it was
measured. The measurement condition is shown below. [0208] Device:
DVS Advantage made by Surface Measurement Systems LTD. [0209]
Measurement point: each 5% from RH95% to RH0%. [0210] Temperature:
25.degree. C.
(Method of Measuring the Karl Fischer Method)
[0211] The moisture was tested by the Japanese Pharmacopoeia
General Tests moisture (coulometric titration). However, an anolyte
was used Aquamicron (registered trademark) AX manufactured by
Mitsubishi Chemical Corporation, and a catholyte was used
Aquamicron (registered trademark) CXU. Scince the water measurement
by Karl Fischer method can be occurred errors within a range of
.+-.0.3%, the value of the water content has to be understood as
including values within a range of about .+-.0.3%.
(Measuring Method by Capillary Electrophoresis Method, CE
Method)
[0212] It is a method by using Capillary Zone Electrophoresis
technique and a method of separation by using free electrophoresis
of each sample component in a buffer including electrolyte.
[0213] After injecting a compound solution to fused silica
capillary filling a buffer adjusting the pH 2.5 to 11.5, high
voltage (Inlet side +, Outlet side -) is on capillary, and then a
compound moves at a speed reflecting an ionized state at the pH of
the buffer (a compound having (+) charge moves quickly, and a
compound having (-) charged moves slowly). pKas was calculated by
plotting the difference between the migration time of the compound
and that of a nutral molecule (DMSO) against pH, and fitting.
Measurement condition is shown below. [0214] Device: Beckman P/ACE
system MDQ PDA [0215] Running solution: pH 2.5 to 11.5 Buffer (10
vol % including MeOH) [0216] Sample solution: Mixture of 10 .mu.L
of Blank DMSO and 90 .mu.L of water 10 mM of Sample in 4 uL of DMSO
stock solution, 6 uL of DMSO and 90 uL of water
(Method)
[0216] [0217] Capillary: Fused silica capillary (BECKMAN COULTER,
Internal diameter 50 .mu.m, Total length 30.2 cm, Effective length
20.0 cm) [0218] Applied voltage: 10 kV (331 V/cm) [0219] Applied
air pressure: 0.7 psi [0220] Capillary temperature: 25.degree. C.
[0221] Electroosmotic flow marker: DMSO [0222] Detecting:
Multiwavelength ultra violet absorption detection (Measurement
wavelength; 215 nm, 238 nm) [0223] Sample injection: Pressure
method (0.5 psi, 5 sec) As used herein, pKa is the pKa at
25.degree. C., pKa means the pKa of the lowest value in a case of
an acid having a plurality of pKa values.
Synthesis Example 1
Synthesis of the Compound (IA)
[0224] The compound (IA) was prepared according to the method
described in WO2010/050468. As a result of measurement of the pKa
values of the compound (IA), pKa1 was 4.2 and pKa2 was 7.2.
Example 1
[0225] Preparation of a Seed Crystal A of 2 Mole Equivalents of
p-toluenesulfonic Acid Salt of the Compound (IA)
[0226] The compound (IA) (100 mg) was dissolved in 1.0 mol/L
p-toluenesolufonic acid solution (2 mL) at room temperature using
an ultrasonic, and the resulting solution was left to stand at
4.degree. C., for 4 days. The precipitate was filtered to yield a
seed crystal A (73 mg). It was confirmed to be a needle-like
crystal by microscope.
Example 2
[0227] Preparation of a Crystalline Solid of 4-hydrates of 2 Mole
Equivalents of p-toluenesulfonic Acid Salt of the Compound (IA)
[0228] The compound (IA) (2.00 g) was dissolved in
p-toluenesulfonic acid monohydrate (7.58 g), acetonitrile (5 mL)
and water (5 mL). Water (30 mL) was further added to the solution.
To the solution was added a piece of the seed crystal A, and the
resulting solution was left to stand at room temperature for three
hours and at 5.degree. C. for 16 hours. The precipitate was
filtered and washed with cold water, and then dried for 45 minutes
while blowing dry nitrogen gas to yield a crystalline solid (2.00
g). [0229] Elemental analysis: (calculated as
C.sub.30H.sub.34ClN.sub.7O.sub.10S.sub.2 2.00.sub.7H.sub.8O.sub.3S
4.0H.sub.2O) [0230] Calculated: C 45.22(%), H 5.00(%), N 8.39(%),
Cl 3.03(%), S 10.97(%), H.sub.2O 6.17(%) [0231] Measured: C
45.22(%), H 4.91(%), N 8.25(%), Cl 2.86(%), S 11.23(%), H.sub.2O
(KF method) 6.21(%) In the X-ray powder diffraction spectrum
measured by Measurement condition 1, the peaks at diffraction angle
(2.theta.): 5.1.+-.0.2.degree., 8.2.+-.0.2.degree.,
12.1.+-.0.2.degree. and 13.9.+-.0.2.degree. were obserbed.
Example 3
[0232] Preparation of a Crystalline Solid of 8.5-hydrate of 2 Mole
Equivalents of p-toluenesulfonic Acid Salt of the Compound (IA)
[0233] The compound (IA) (2.00 g) was dissolved in
p-toluenesulfonic acid mono-hydrate (7.58 g), acetone (5 mL) and
water (5 mL). Water (30 mL) was further added to the solution. To
the solution was added a piece of the seed crystal A, and the
resulting solution was left to stand at room temperature for 3
hours and at 5.degree. C. for 16 hours. The precipitate was
filtered and washed with cold water, and then dried for 45 minutes
while blowing dry nitrogen gas to yield a crystalline solid (2.30
g). [0234] Elemental analysis: (calculated as
C.sub.30H.sub.34ClN.sub.7O.sub.10S.sub.2 2.00.sub.7H.sub.8O.sub.3S
8.5H.sub.2O) [0235] Calculated: C 42.28(%), H 5.40(%), N 7.84(%),
Cl 2.84(%), S 10.26(%), H.sub.2O 12.25(%) [0236] Measured: C
42.37(%), H 5.26(%), N 7.79(%), Cl 2.70(%), S 10.69(%), H.sub.2O
(KF method) 12.11(%) The result of the X-ray powder diffraction
measured by Measurement condition 1 is shown in FIG. 1 and Table
1.
TABLE-US-00001 [0236] TABLE 1 Diffraction angle 2.theta. (.degree.)
5.3 8.1 8.9 10.4 10.9 13.3 17.4 19.1 20.0 21.3 24.4 25.1 26.2 27.7
29.0
Example 4
[0237] Preparation of a Crystalline Solid of a Mixed Acid Salt of
the Compound (IA), Wherein the Mixed Salt is formed from 1 Mole
Equivalent of p-toluenesuifonic Acid and 1 Mole Equivalent of
Hydrochloric Acid
[0238] The seed crystal A (50 mg) was dissolved in 6 mol/L HCl (0.5
mL) on an ultrasonic water bath at room temperature. After adding 1
mol/L HCl (2 mL) to the solution, the solution was left to stand at
4.degree. C. for 2 days. The precipitated solid was filtered and
washed with ice chilled water to yield a crystalline solid (23 mg).
It was confirmed to be a crystalline solid by microsope.
The result of an X-ray powder diffraction measured by Measurement
condition 1 is shown in FIG. 2 and Table 2.
TABLE-US-00002 TABLE 2 Diffraction angle 2.theta. (.degree.) 8.5
10.2 11.6 13.1 16.5 19.2 20.3 24.6 26.2 27.8 33.0
Example 5
[0239] Preparation of a Crystalline Solid of the Mixed Acid Salt of
the Compound (IA), Wherein the Mixed Acid Salt was formed from 1
Mole Equivalent of p-toluenesulfonic Acid and 1 Mole Equivalent of
Hydrobromic Acid
[0240] The seed crystal A (50 mg) was dissolved in 6 mol/L HBr
aqueous solution (0.25 mL) on the ultrasonic water bath at room
temperature. After adding 1 mol/L HBr aqueous solution (2 mL), the
solution was left to stand at 4.degree. C. for 2 days. The
precipitated solid was filtered and washed with ice chilled water
to yield a crystalline solid (11 mg). It was confirmed to be a
crystalline solid by microscope.
The result of the X-ray powder diffraction measured by Measurement
condition 1 is shown in FIG. 3 and Table 3.
TABLE-US-00003 TABLE 3 Diffraction angle 2.theta. (.degree.) 8.5
10.3 13.2 16.6 19.3 20.3 22.0 24.7 26.3 27.8 29.6 33.0
Example 6
[0241] Preparation of the Type I Crystal: a Crystalline Solid of
Hydrate of a Mixed Acid Salt of the Compound (IA), Wherein the
Mixed Acid Salt was formed from 1.3 Mole Equivalents of
p-toluenesulfonic Acid and 0.35 Mole Equivalents of Sulfuric
Acid
Example 6-1
Synthesis of the Type I Crystal D
Step 1: Preparation of a Seed Crystal C
[0242] The seed crystal A (50 mg) was dissolved in 6 mol/L
H.sub.2SO.sub.4 (3 mL) on an ultrasonic water bath at room
temperature, and the solution was left to stand at 4.degree. C. for
2 days. The precipitated crystalline solid was filtered and washed
with ice chilled water to yield a seed crystal C (23 mg).
Step 2: Synthesis of the Compound (IA) and Preparation of the Type
I Crystal D
##STR00007##
[0244] Under a nitrogen atmosphere, the compound 1 (18.0 kg, 22.6
mol) was dissolved in N, N-dimethylacetoamide (41 L), and cooled to
0.degree. C. Sodium iodide (6.8 kg, 45.2 mol), the compound 2 (13.1
kg, 24.9 mol), and N,N-dimethylacetoamide (4 L) are added to the
solution at 0.degree. C. for 6 days. The solution was warmed to
7.degree. C., and stirred for 16 hours. The solution was cooled to
0.degree. C. and sodium iodide (5.1 kg, 33.9 mol) was added to the
solution, and then acetyl chloride (8.9 kg, 113.0 mol) was dropped
over 90 minutes at 0.degree. C., the solution was stirred at
0.degree. C. for 5 hours. [0245] Anisole (36 L) was added to the
reaction solution, this solution was added to the mixed solution of
methyl ethyl ketone and aqueous solution of sodium bisulfite, and
extracted. The organic layer was washed with the mixed solution of
sulfuric acid and brine twice. [0246] Anisole (90 L) was added and
the solution was cooled to 15.degree. C. 75% sulfuric acid (36.0
kg) was added to the solution, it was stirred at 28.degree. C. for
2 hours. After adding water (90 L) and ethyl acetate (36 L), the
resulting solution was extracted. The obtained aqueous layer was
washed with ethyl acetate twice, and then purified by reverse phase
column chromatography (acetonitrile-sulfuric acid aqueous solution)
using a chromatographic separation small particle size synthetic
adsorbent (Diaion.TM. HP20SS). After adding an aqueous solution of
75% sulfuric acid (33.4 kg) and p-toluenesulfonic acid monohydrate
(16.7 kg), it was added an appropriate amount of the seed crystal C
to precipitate a solid. It was cooled to 5.degree. C. and stirred
at 5.degree. C. for 10 hours, and the precipitated crystalline
solid was filtered. The crystalline solid was washed with water
cooled to 5.degree. C., and then dried under reduced pressure at
about 33 hPa for about 3 hours to yield a type I crystal D of the
compound (IA) (12.7 kg, content conversion yield: 49%).
[0247] The contents of p-toluenesulfonic acid and sulfuric acid in
the type I crystal D were determined by the following method.
(p-Toluenesulfonic Acid Content Measuring Method)
Step 1: Preparation of a Sample Solution
[0248] About 40 mg of the sample was weighed precisely, and
dissolved in a sample dilution solvent to be exactly 25 mL. To 2 mL
of this solution weighed precisely was added a sample dilution
solvent to be prepared exactly 20 mL solution.
Step 2: Preparation of a Standard Solution
[0249] About 25 mg of a standard preparation of sodium
p-toluenesulfonate equilibrated humidity under the condition of
25.degree. C./60% RH was weighed precisely, and dissolved in a
sample dilution solvent to be exactly 100 mL. To 5 mL of this
solution weighed precisely was added a sample dilution solvent to
be prepared exactly 50 mL solution.
[0250] 5 mmol/L phosphate buffer/liquid chromatography acetonitrile
mixture (9:1) was used as the above sample dilution solvent.
Herein, water: 0.05 mol/L sodium dihydrogen phosphate test
solution: 0.05 mol/L disodium hydrogen phosphate reagent
mixture=18:1:1 (pH is about 7.1) was used as a phosphate
buffer.
Step 3: Measurement and Determination
[0251] The peak area of p-toluenesulfonic acid was determined in an
automatic integration method by measuring the above sample solution
and the standard solution in the following test condition by liquid
chromatography. Note that an anhydrous basis (a dehydration product
conversion) is caluculated values omitted the water content from
the total amount as 100%.
(Test Condition)
[0252] Column: Unison UK-C18, .phi.4.6.times.150 mm, 3 .mu.m, by
Imtakt [0253] Column temperature: constant temperature at near
35.degree. C. [0254] Flow rate: 1.0 mL per minute (a retention time
of p-toluenesulfonic acid: about 7 minutes) [0255] Detector:
ultraviolet absorption spectrophotometer (wavelength: 218 nm)
[0256] Mobile phase A: 0.1% trifluoroacetic acid solution [0257]
Mobile phase B: acetonitrile for liquid chromatography [0258]
Gradient program
TABLE-US-00004 [0258] Time after addition Mobile phase A Mobile
phase B (minute) (vol %) (vol %) 0~7 95 5 7~7.01 95.fwdarw.60
5.fwdarw.40 7.01~15 60 40 15~15.01 60.fwdarw.95 40.fwdarw.5
15.01~25 95 5
The content of p-toluenesulfonic acid in the sample was determined
using the following formula.
The amount of p - toluenesulfonic acid ( % ) = M S M T .times. P
100 .times. 100 100 - W T .times. A T A S .times. 172.20 194.18
.times. 1 4 .times. 100 ##EQU00001## [0259] M.sub.S: weighed amount
of a standard preparation of sodium p-toluenesulfonate (mg) [0260]
M.sub.T: weighed amount of a sample (mg) [0261] P: purity of a
standard preparation of sodium p-toluenesulfonate (%) [0262]
W.sub.T: water of a sample (%) [0263] A.sub.T: peak area of
p-toluenesulfonic acid obtained from the sample solution [0264]
A.sub.S: peak area of p-toluenesulfonic acid obtained from the
standard solution [0265] 172.20: molecular weight of
p-toluenesulfonic acid [0266] 194.18: molecular weight of sodium
p-toluenesulfonate [0267] 1/4: dilution rate
(Sulfuric Acid Content Measuring Method)
Step 1: Preparation of a Standard Solution
[0268] About 50 mg of sodium sulfate anhydrous was weighed
precisely, and dissolved in a mobile phase to be exactly 25 mL. To
2 mL of this liquid weighed precisely was added a mobile phase to
be exactly 50 mL. Furthermore, to 2 mL of this liquid weighed
precisely was added a mobile phase to be exactly 20 mL.
Step 2: Preparation of a Sample Solution
[0269] About 30 mg of a sample was weighed precisely, and dissolved
in a mobile phase to be exactly 25 mL. To 2 mL of this liquid
weighed precisely was added a mobile phase to be exactly 20 mL.
Step 3: Measurement and Determination
[0270] The peak area of sulfate ion was determined in an automatic
integration method by measuring the above sample solution and the
standard solution in the following test condition by liquid
chromatography.
(Test Condition)
[0271] Column: Shim-pack IC-A3, .phi.4.6.times.150 mm, 5 .mu.m,
Shimadzu Corporation [0272] Column temperature: constant
temperature at near 40.degree. C. [0273] Flow rate: 1.2 mL per
minute (a retention time of sulfate ion: about 15 minutes) [0274]
Detector: electric conductivity detector (non-suppressor system)
[0275] Mobile phase: the solution obtained by the following: about
0.67 g of Bis-Tris, about 3.09 g of boric acid, and about 1.11 g of
the ground p-hydroxybenzoic acid weighed precisely were dissolved
in water to be exactly 1000 mL. The content of sulfuric acid in the
sample was determined using the following formula.
[0275] The amount of sulfuric acid
(%)=M.sub.S/M.sub.T.times.100/(100-W.sub.T).times.A.sub.T/A.sub.S.times.9-
8.08/142.04.times.1/25.times.100 [0276] M.sub.S: weighed amount of
sodium sulfate anhydrous (mg) [0277] M.sub.T: weighed amount of a
sample (mg) [0278] W.sub.T: water of a sample (%) [0279] A.sub.S:
peak area of sulfate ion obtained from the standard solution [0280]
A.sub.T: peak area of sulfate ion obtained from the sample solution
[0281] 98.08: molecular weight of sulfuric acid [0282] 142.04:
molecular weight of sodium sulfate anhydrous [0283] 1/25: dilution
rate
(Result)
[0283] [0284] p-Toluenesulfonic acid: 22.2.+-.0.2% (on an anhydrous
basis) [0285] Sulfuric acid: 4.3.+-.0.1% (on an anhydrous basis)
[0286] Elemental analysis: (calculated as
C.sub.30H.sub.34N.sub.7ClO.sub.10S.sub.2 1.32C.sub.7H.sub.8O.sub.3S
0.45H.sub.2SO.sub.4 9.0H.sub.2O) [0287] Calculated: C 39.75(%), H
5.39(%), N 8.27(%), C1 2.99(%), S 10.19(%), H.sub.2O 13.67(%)
[0288] Measured: C 39.73(%), H 5.33(%), N 8.53(%), C1 3.08(%), S
10.11(%), H.sub.2O (KF method) 13.69(%) The result of the X-ray
powder diffraction measured by Measurement condition 2 is shown in
FIG. 4 and Table 4. It should be noted that an aluminium plate as a
sample folder. The peak whose 2-theta (2.theta.) value is around
38.degree. is the peak of aluminium.
TABLE-US-00005 [0288] TABLE 4 Diffraction angle 2.theta. (.degree.)
8.3 9.0 10.1 11.5 13.0 16.3 17.3 18.1 19.1 19.9 20.3 20.8 21.6
26.2
[0289] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 9.0.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree., 16.3.+-.0.2.degree.,
17.3.+-.0.2.degree., 18.1.+-.0.2.degree., 19.1.+-.0.2.degree.,
20.3.+-.0.2.degree. and 26.2.+-.0.2.degree.. Preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree.,
16.3.+-.0.2.degree. and 20.3.+-.0.2.degree.. Further preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
Example 6-2
Synthesis of the Type I Crystal E
[0290] The type I crystal D (25.0 g) obtained by the method
described in Example 6-1 was suspended in water cooled to 5.degree.
C. (125 mL) and stirred for 26 hours at 5.degree. C., and the
precipitated crystalline solid was filtered. The crystalline solid
was washed with water cooled to 5.degree. C. (75 mL) to yield a
type I crystal E of the compound (IA) (22.92 g).
[0291] The contents of p-toluenesulfonic acid and sulfuric acid in
the type I crystal E were determined by the method described in the
above Example 6-1.
(Result)
[0292] p-Toluenesulfonic acid: 21.9.+-.0.2% (on an anhydrous basis)
[0293] Sulfuric acid: 3.9.+-.0.1% (on an anhydrous basis) [0294]
Elemental analysis: (calculated as
C.sub.30H.sub.34N.sub.7ClO.sub.10S.sub.2 1.300.sub.7H.sub.8O.sub.3S
0.35H.sub.2SO.sub.4 9.0H.sub.2O) [0295] Calculated: C 40.05(%), H
5.42(%), N 8.36(%), C1 3.02(%), S 9.98(%), H.sub.2O 13.82(%) [0296]
Measured: C 39.96(%), H 5.32(%), N 8.59(%), C1 2.99(%), S 10.11(%),
H.sub.2O (KF method) 13.78(%). The result of the X-ray powder
diffraction measured by Measurement condition 2 is shown in FIG. 5
and Table 5. It should be noted that an aluminium plate as a sample
folder. The peak whose 2-theta (2.theta.) value is around
38.degree. is the peak of aluminium.
TABLE-US-00006 [0296] TABLE 5 Diffraction angle 2.theta. (.degree.)
8.3 9.0 10.1 11.5 13.0 16.3 17.3 18.1 19.1 19.9 20.3 20.8 21.6
26.2
[0297] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are, 8.3.+-.0.2.degree., 9.0.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree., 16.3.+-.0.2.degree.,
17.3.+-.0.2.degree., 18.1.+-.0.2.degree., 19.1.+-.0.2.degree.,
20.3.+-.0.2.degree. and 26.2.+-.0.2.degree.. Preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree.,
16.3.+-.0.2.degree. and 20.3.+-.0.2.degree.. Further preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0298] As described above, although there is a difference of the
content of p-toluenesulfonic acid and sulfuric acid between the
type I crystal D and the type I crystal E, they are same
crystalline form scince they have the same X-ray powder diffraction
pattern. That is, the type I crystal D is a crystalline solid
remaining about 0.02 mole equivalents of p-toluenesulfonic acid and
about 0.1 mole equivalent of sulfuric acid with the type I crystal
E.
[0299] The type I crystal may contain remaining about 0.01 to 0.1
mole equivalents of p-toluenesulfonic acid and/or about 0.01 to 0.1
mole equivalents of sulfuric acid. The remaining acid may be in the
form adhered to a crystal or the form incorporated into a
crystal.
[0300] The preferable content of p-toluenesulfonic acid of the type
I crystal is about 20.2.+-.0.2 to 23.2.+-.0.2% (on an anhydrous
basis), the preferable content of sulfuric acid is about 3.5.+-.0.1
to 5.0.+-.0.1% (on an anhydrous basis). The more preferable content
of p-toluenesulfonic acid is about 21.5.+-.0.2 to 22.3.+-.0.2% (on
an anhydrous basis), the more preferable content of sulfuric acid
is about 4.2.+-.0.1 to 4.9.+-.0.1% (on an anhydrous basis). The
further preferable content of p-toluenesulfonic acid of the type I
crystal is about 21.5 to 22.3% (on an anhydrous basis), further
preferable content of sulfuric acid is about 4.2 to 4.9% (on an
anhydrous basis).
Example 7
Preparation of a Crystalline Solid of 2 Mole Equivalents of
Benzenesulfonic Acid Salt of the Compound (IA)
[0301] The betaine of the compound (IA) (100 mg) was dissolved in
1.0 mol/L benzenesulfonate aqueous solution (5.5 mL) at room
temperature using ultrasonic. To the solution was added a piece of
the seed crystal A, the solution was left to stand at 5.degree. C.
for 4 days. The precipitate was filtered to obtain a seed crystal B
(27 mg).
[0302] The betaine of the compound (IA) (300 mg) was dissolved in
acetonitrile (0.30 mL) and water (0.75 mL), and benzenesulfonic
acid (949 mg) was added to the solution. After further adding water
(3.0 mL) to the solution, a piece of seed crystal B was added to
the solution, and the solution was left to stand at 5.degree. C.
for 5 days. The precipitate was filtered to yield a crystalline
solid (79.8 mg).
[0303] The results of the X-ray powder diffraction measured by
Measurement condition 1 were shown in FIG. 6 and Table 6.
TABLE-US-00007 TABLE 6 Diffraction angle 2.theta. (.degree.) 8.4
9.2 10.3 11.6 13.3 16.5 19.2 19.6 20.3 20.8 22.1 23.6 24.5 25.2
26.3 31.2 32.4 33.1 34.3
Example 8
Measurement of Dynamic Vapor Sorption of the Type I Crystal D and
X-Ray Powder Diffraction in Each Humidity
[0304] The results of a dynamic vapor sorption measurement of the
type I crystal D obtained in Example 6-1 were shown in FIG. 7 and
Table 7. Dynamic vapor sorption measurement can be occurred errors
within the range of .+-.0.5%. An increased amount of water (%)
represents an increased amount of the type I crystal at 0% RH.
TABLE-US-00008 TABLE 7 Relative humidity Increased amount (% RH) of
water (%) 0 0.00 5 3.33 10 5.26 15 7.70 20 10.53 25 11.67 30 12.28
35 12.75 40 13.16 45 13.54 50 13.91 55 14.25 60 14.55 65 14.93 70
15.26 75 15.55 80 15.82 85 16.08 90 16.34 95 16.60
[0305] The results of X-ray powder diffraction measured by
Measurement condition 3 using the type I crystal D which is held
for 3 hours or more at each relative humidity conditions were shown
below.
[0306] The result of X-ray powder diffraction at 30% RH conditions
is shown in FIG. 8 and Table 8.
TABLE-US-00009 TABLE 8 Diffraction angle 2.theta. (.degree.) 8.4
9.1 10.2 11.6 13.0 16.4 17.4 18.2 19.2 20.1 20.4 26.2 27.8
[0307] The diffraction angels (2.theta.) showing characteristic
diffraction peaks are 8.4 .+-.0.2.degree., 9.1.+-.0.2.degree.,
10.2.+-.0.2.degree., 11.6.+-.0.2.degree., 13.0.+-.0.2.degree.,
20.1.+-.0.2.degree., 20.4.+-.0.2.degree. and 26.2.+-.0.2.degree..
Preferable is 8.4.+-.0.2.degree., 10.2.+-.0.2.degree.,
13.0.+-.0.2.degree. and 20.4.+-.0.2.degree..
[0308] The result of the X-ray powder diffraction at 40% RH
conditions is shown in FIG. 9 and Table 9.
TABLE-US-00010 TABLE 9 Diffraction angle 2.theta. (.degree.) 8.4
9.1 10.2 11.5 13.0 16.4 17.4 18.2 19.2 20.0 20.3 20.8 21.7 22.0
23.9 24.6 25.3 26.2 27.8 31.9 33.0
[0309] The diffraction angels (2.theta.) showing characteristic
diffraction peaks are 8.4.+-.0.2.degree., 9.1.+-.0.2.degree.,
10.2.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
20.0.+-.0.2.degree., 20.3.+-.0.2.degree., 21.7.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.4.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0310] The result of X-ray powder diffraction at 50% RH conditions
is shown in FIG. 10 and Table 10.
TABLE-US-00011 TABLE 10 Diffraction angle 2.theta. (.degree.) 8.4
9.1 10.2 11.5 13.0 14.2 14.7 16.4 17.3 18.2 19.2 20.0 20.3 20.8
21.7 22.0 24.0 24.6 25.2 25.7 26.2 27.8
[0311] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.4.+-.0.2.degree., 9.1.+-.0.2.degree.,
10.2.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
20.0.+-.0.2.degree., 20.3.+-.0.2.degree., 21.7.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.4.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0312] The result of X-ray powder diffraction at 60% RH conditions
is shown in FIG. 11 and Table 11.
TABLE-US-00012 TABLE 11 Diffraction angle 2.theta. (.degree.) 8.3
9.1 10.0 10.2 11.5 13.0 14.2 16.3 17.3 18.1 19.1 19.9 20.3 20.5
20.8 21.6 22.1 23.5 23.8 24.3 24.6 25.1 26.2 28.3 28.9 29.4 31.3
32.1 33.1
[0313] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 9.1.+-.0.2.degree.,
10.2.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree., 6.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.3.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0314] The result of X-ray powder diffraction at 70% RH conditions
is shown in FIG. 12 and Table 12.
TABLE-US-00013 TABLE 12 Diffraction angle 2.theta. (.degree.) 8.3
9.0 9.9 10.1 11.5 13.0 14.1 16.1 16.5 17.2 18.1 19.1 19.9 20.3 20.6
20.8 21.6 22.1 23.3 24.2 24.5 25.0 25.5 26.2 28.2 28.8 29.4 31.3
32.2 33.2
[0315] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 0.+-.0.2.degree.,
1.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree., 21.6.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 3.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0316] The result of X-ray powder diffraction at 80% RH conditions
is shown in FIG. 13 and Table 13.
TABLE-US-00014 TABLE 13 Diffraction angle 2.theta. (.degree.) 8.3
9.0 9.7 10.1 11.5 13.0 14.0 16.2 16.5 17.1 18.0 19.1 19.3 19.9 20.3
20.7 21.6 22.2 23.1 23.4 24.1 24.4 24.9 26.2 28.2 28.7 29.3
32.3
[0317] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 0.+-.0.2.degree.,
10.1.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree., 21.6.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.3.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0318] The result of the X-ray powder diffraction at 90% RH
conditions is shown in FIG. 14 and Table 14.
TABLE-US-00015 TABLE 14 Diffraction angle 2.theta. (.degree.) 8.3
9.0 9.6 10.1 11.5 13.1 14.0 15.6 16.1 16.5 17.1 17.9 18.7 19.0 19.4
19.9 20.3 20.8 21.6 22.3 22.9 23.2 23.7 24.3 24.8 26.2 28.1 28.8
29.2 30.3 32.4
[0319] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 9.0.+-.0.2.degree.,
10.1.+-.0.2.degree., 11.5.+-.0.2.degree., 13.1.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree., 21.6.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.3.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.1.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0320] The result of the X-ray powder diffraction at 95% RH
conditions is shown in FIG. 15 and Table 15.
TABLE-US-00016 TABLE 15 Diffraction angle 2.theta. (.degree.) 8.2
9.0 9.6 10.1 11.5 13.0 14.0 15.6 16.0 16.6 17.1 17.9 18.6 19.0 19.4
19.9 20.3 20.8 21.5 22.3 22.8 23.1 24.2 24.7 26.2 28.1 28.8 29.3
32.5
[0321] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.2.+-.0.2.degree., 9.0.+-.0.2.degree.,
10.1.+-.0.2.degree., 11.5.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree., 5.+-.0.2.degree. and
26.2.+-.0.2.degree.. Preferable is 8.2.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
[0322] From the above results, it is suggested that the type I
crystal can come into being adsorption of moisture by change of
relative humidity to make hydration water, and the most hydration
water is incorporated in the crystal lattice as crystal water. In
other words, the type I crystal is the crystalline solid that water
molecules can easily move in and out through the crystal lattice as
crystal water depending on an external humidity change. That is, as
shown in FIGS. 7 to 15, the type I crystal is a crystalline solid
wherein the number of its hydration water can change at the degree
to hold several hours under different humidity environment, and
these type I crystals can be substantially interpreted as the same
crystalline solid even if they are different in the number of
hydration water, that is different composition in the content of
water. The hydration water may be crystal water, adhere water, or
residual solvent.
[0323] A preferred content of water of the type I crystal is about
12 to 17%, more preferable is about 12 to 15%. A preferred
hydration water of the type I crystal is about 7 to 12 mole, more
preferable is about 8 to 11.5 mole.
[0324] These type I crystals having different content of water have
characteristic diffraction peaks in common. The diffraction angels
(2.theta.) showing characteristic diffraction peaks are
8.2.+-.0.2.degree., 8.9.+-.0.2.degree., 10.1.+-.0.2.degree.,
11.4.+-.0.2.degree., 13.0.+-.0.2.degree., 19.9.+-.0.2.degree.,
20.3.+-.0.2.degree., 21.5.+-.0.2.degree. and 26.2.+-.0.2.degree..
Preferable is 8.2.+-.0.2.degree., 8.9.+-.0.2.degree.,
10.1.+-.0.2.degree., 11.4.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.9.+-.0.2.degree., 20.3.+-.0.2.degree. and 26.2.+-.0.2.degree..
More preferable is 8.2.+-.0.2.degree., 10.1.+-.0.2.degree.,
13.0.+-.0.2.degree. and 20.3.+-.0.2.degree..
Example 9
Preparation of Sodium Salt of the Compound (IA)
##STR00008##
[0325] Step 1 Synthesis of the Compound 8
[0326] The compound 6 (970 g, 713 mmol, 78 w/w % purity) was
dissolved in dichloromethane (7.13 L), the compound 7 was added at
15.degree. C. as internal temperature to the solution. The
suspension was cooled to -25.degree. C., and EDC hydrochloride
(150.35 g, 784 mmol) and pyridine (46 mL, 570 mmol) were added, and
then the reaction solution was stirred at -20.degree. C. for 3
hours. The reaction solution was added to the mixed solution of 2
mol/L hydrochloric acid (285 mL), cold-water(7.2 L), and ethyl
acetate (2.4 L), the dichloromethane was distilled off under
reduced pressure. To the obtained solution was added ethyl acetate
(4.5 L), the resulting solution was washed with brine twice. The
organic layer was concentrated under reduced pressure to yield a
crude product containing the compound 8 (1250 g). The crude product
containing the compound 8 was used in the next step without
purification.
Step 2 Synthesis of the Compound 8
[0327] To anisole (1.54 L) cooling in dry ice-ethanol bath was
added aluminium chloride (495.4 g, 3.71 mol) followed by
dichloromethane. 610 g of the crude product containing the compound
8 obtained by Step1 was dissolved in a mixed solution of
dichloromethane (0.51 L) and anisole (1.03 L) and spent 1 hour
adding dropwise to the above aluminium chloride solution re-cooling
to -40.degree. C. The container used for the dropwise was washed
with a mixed solution of dichloromethane (0.36 L) and anisole (0.51
L) and the wash fluid was added to the reaction solution. The
reaction solution was stirred at -20.degree. C. for 2 hours, and
added to a mixed solution of ethanol (7.1 L), 1 mol/L hydrochloric
acid (7.1 L) while stirring under cooling in ice-bath. The mixed
solution was stirred for 30 minutes under ice-cooling,
dichloromethane (5.14 L) and satirated brine (257 mL) was added,
the separated aqueous layer was washed with dichloromethane (5.14
L). The organic layer was extracted with a mixture of water (2.57
L) and saturated brine (100 mL), and the separated aqueous layer
was combined with the previous aqueous layer. The aqueous layer was
stirred under cooling in ice-bath, and 2 mol/L sodium hydroxide
aqueous solution was added to adjust pH to 1.5 and the solution was
left to stand. The aqueous layer was concentrated and purified by
HP20SS column (eluent: 13% acetonitrile water). Sodium bicarbonate
(8.75 g) was added to the collected fractions containing the target
product and the resulting solution was concentrated under reduced
pressure until 500 mL. The solution was diluted by adding water
(1.6 L) and filted with cotton plug, and then the filtrate was
lyophilized to yield the compound 9 (77.8 g). [0328] Elemental
analysis: (calculated as C.sub.30H.sub.33ClN.sub.7O.sub.10S.sub.2Na
4.5H.sub.2O) [0329] Calculated: C; 42.13, H; 4.95, N; 11.46, S;
7.50, Cl; 4.14, Na; 2.69 (%) [0330] Measured: C; 42.22, H; 4.88, N;
11.24, S; 7.01, Cl; 4.04, Na; 2.74 (%) The solubility of the
obtained compound 9 in various aqueous medium (water for injection,
saline, dextrose solution) was all 100 mg/mL or more, and they are
very high solubility.
Example 10
[0331] Preparation of a Crystalline Solid of a Mixed Acid Salt of
the Compound (IA), Wherein the Mixed Acid is formed from 1 Mole
Equivalent of p-toluenesulfonic Acid and 1 Mole Equivalent of
Nitric Acid
[0332] A seed crystal A (20 mg) obtained in the same manner as in
Example 1 was dissolved in 2 mol/L HNO3 aqueous solution (0.3 mL).
The solution was left to stand at 4.degree. C. for 2 days. The
precipitated solid was collected to yield a crystalline solid. It
was confirmed to be a crystalline solid by using the
microscope.
[0333] The result of X-ray powder diffraction measured by
Measurement condition 1 is shown in Table 1.
TABLE-US-00017 TABLE 16 Diffraction angle 2.theta. (.degree.) 8.5
9.4 10.6 20.0 20.4 24.9
Example 11
[0334] Preparation of a Crystalline Solid of a Mixed Acid Salt of
the Compound (IA), Wherein the Mixed Acid Salt is formed from 1.05
Mole Equivalents of p-toluenesulfonic Acid and 0.65 Mole
Equivalents of Sulfuric Acid Preparation of a Crystalline Solid of
9 Hydrates of a Mixed Acid Salt of the Compound (IA), Wherein the
Mixed Acid Salt is formed from 1.05 Mole Equivalents of
p-toluenesulfonic Acid and 0.65 Mole Equivalents of Sulfuric
Acid
[0335] The type I crystal D (2.00 g) obtained by the method
according to Example 6-1 was dissolved in 50% acetonitrile aqueous
solution (10 mL), water (40 mL) and 75% sulfiric acid (4.0 g) was
added, the solution was stirred at 15.degree. C. for 5 hours 20
minutes. The solution was cooled to 0.degree. C., stirred for 1
hour 10 minutes, and left to stand for 14 hours 10 minutes in a
refrigerator. The precipitated crystal was filtered, washed with
cold water (6 mL), and air-dried to yield a crystalline solid (1.74
g).
[0336] The obtained crystalline solid (1.5 g) was dissolved in 50%
acetonitrile aqueous solution (7.5 mL), water (30 mL) and 75%
sulfuric acid (3.0 g) were added, and the solution was stirred at
15.degree. C. for 3 hours 30 minutes. The solution was cooled to
0.degree. C. and stirred for 3 hours, and then left to stand for 14
hours 50 minutes at a refrigerator. The precipitated crystalline
solid was filtered, washed with cold water (4.5 mL) and air-dried
to yield a crystalline solid (1.17 g).
[0337] The water content measurement was measured by the Karl
Fischer method. The content of p-toluenesulfonic acid and sulfuric
acid were measured in the same manner as described in Example
6-1.
(Result)
[0338] Water content: 14.0.+-.0.3% [0339] p-Toluenesulfonic acid:
18.2.+-.0.2% (on an anhydrous basis) [0340] Sulfuric acid:
6.4.+-.0.1% (on an anhydrous basis) According to the above results,
the crystalline solid is C.sub.30H.sub.34N.sub.7ClO.sub.10S.sub.2
1.05C.sub.7H.sub.8O.sub.3S 0.65H.sub.2SO.sub.4 9.0H.sub.2O.
[0341] The result of the X-ray powder diffraction measured by
Measurement condition 1 is shown in FIG. 16 and Table 17.
TABLE-US-00018 TABLE 17 Diffraction angle 2.theta. (.degree.) 8.4
9.1 10.2 11.6 13.1 14.2 16.3 17.3 19.2 20.1 20.4 21.7 26.3
[0342] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.4.+-.0.2.degree., 9.1.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.1.+-.0.2.degree., 16.3.+-.0.2.degree.,
17.3.+-.0.2.degree., 19.2.+-.0.2.degree., 20.4.+-.0.2.degree. and
26.3.+-.0.2.degree.. Preferable is 8.4.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.1.+-.0.2.degree., 16.3.+-.0.2.degree. and
20.4.+-.0.2.degree.. Further preferable is 8.4.+-.0.2.degree.,
10.2.+-.0.2.degree., 13.1.+-.0.2.degree. and
20.4.+-.0.2.degree..
Example 12
[0343] A Crystalline Solid of Hydrate of a Mixed Acid Salt of the
Compound (IA), Wherein the Mixed Acid Salt is formed from 1.0 Mole
Equivalent of p-toluenesulfonic Acid and 0.5 Mole Equivalents of
Sulfuric Acid
[0344] The type I crystal D (50.0 g) obtained by the method
described in Example 6-1 was dissolved in a mixture of ethanol (300
mL) and water (200 mL). A mixed solution of 75% sulfuric acid (100
g) and water (500 mL) was added at room temperature, and then water
(400 mL) was further added. The solution was cooled to 0.degree. C.
and stirred for 6 hours to precipitate a crystal, and the
precipitated crystalline solid was filterd. The crystal was washed
with water cooled to 5.degree. C. (600 mL) to yield a crystalline
solid (26.8 g).
[0345] The contents of p-toluenesulfonic acid and sulfuric acid of
the obtained crystalline solid were quantified by the method
described in Example 6-1.
(Result)
[0346] p-Toluenesulfonic acid: 18.3.+-.0.2% (on an anhydrous basis)
[0347] Sulfuric acid: 4.9.+-.0.1% (on an anhydrous basis) [0348]
Elemental analysis: (calculated as
C.sub.30H.sub.34N.sub.7ClO.sub.10S.sub.2 1.0C.sub.7H.sub.8O.sub.3S
0.5H.sub.2SO.sub.4 10.0H.sub.2O) [0349] Calculated: C 38.52(%), H
5.50(%), N 8.50(%), Cl 3.07(%), S 9.73(%), H.sub.2O 15.61(%) [0350]
Measured: C 38.69(%), H 5.31(%),N 8.67(%), Cl 3.04(%), S 9.84(%),
H.sub.2O (KF method) 15.85(%).
[0351] The result of the X-ray powder diffraction measured by
Measurement condition 2 isshown in FIG. 17 and Table 18. It should
be noted that the aluminium plate is used as a sample folder. The
peak whose 2-theta (2.theta.) value is around 38.degree. is the
peak of aluminium.
TABLE-US-00019 TABLE 18 Diffraction angle 2.theta. (.degree.) 8.3
9.0 10.1 11.5 13.0 16.5 17.2 18.1 19.1 20.0 20.3 20.9 21.7 26.3
[0352] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 8.3.+-.0.2.degree., 9.0.+-.0.2.degree.,
10.1.+-.0.2.degree., 13.0.+-.0.2.degree., 16.5.+-.0.2.degree.,
17.2.+-.0.2.degree., 18.1.+-.0.2.degree., 19.1.+-.0.2.degree.,
20.3.+-.0.2.degree. and 26.3.+-.0.2.degree.. Preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree.,
16.5.+-.0.2.degree. and 20.3.+-.0.2.degree.. Further preferable is
8.3.+-.0.2.degree., 10.1.+-.0.2.degree., 13.0.+-.0.2.degree. and
20.3.+-.0.2.degree..
Example 13
[0353] Synthesis of a Crystalline Solid of Hydrate of 2 Mole
Equivalents of p-toluenesulfonic Acid Salt of the Compound (IA)
[0354] The type I crystal D (25.9 g) obtained by the method
described in Example 6-1 was dissolved in a mixture of acetonitrile
(40 mL) and water (40 mL). Water (259 mL) was further added, and
p-toluenesulfonic acid monohydrate (103.5 g) was added. The
solution was cooled to 5.degree. C. and left to stand for 65 hours,
the precipitated crystalline solid was filtered. The crystal was
washed with water cooled to 5.degree. C. (80 mL) to yield a
crystalline solid (15.0 g).
[0355] The contents of p-tolunesulfonic acid and sulfuric acid of
the obtained crystalline solid was quantified by the method
described in the above Example 6-1.
(Result)
[0356] p-Toluenesulfonic acid: 31.3.+-.0.2% (on an anhydrous basis)
[0357] Sulfuric acid: 0.0.+-.0.1% (on an anhydrous basis) [0358]
Elemental analysis: (calculated as
C.sub.30H.sub.34N.sub.7ClO.sub.10S.sub.2 2.0C.sub.7H.sub.8O.sub.3S
10.5H.sub.2O) [0359] Caluculated: C 41.10(%), H 5.57(%),N 7.63(%),
C1 2.76(%), S 9.97(%), H.sub.2O 14.71(%) [0360] Measured: C
40.82(%), H 5.43(%),N 7.75(%), C1 2.83(%), S 10.05(%), H.sub.2O (KF
method) 14.91(%).
[0361] The result of the X-ray powder diffraction measured by
Measurement condition 2 is shown in FIG. 18 and Table 19. It should
be noted that the aluminium plate is used as a sample folder. The
peak whose 2-theta (2.theta.) value is around 38.degree. is the
peak of aluminium.
TABLE-US-00020 TABLE 19 Diffraction angle 2.theta. (.degree.) 5.3
8.0 8.8 10.5 10.9 13.1 17.4 19.0 19.7 20.3 21.3 24.4 25.1 26.3 27.6
29.0
[0362] The diffraction angles (2.theta.) showing characteristic
diffraction peaks are 5.3.+-.0.2.degree., 8.0.+-.0.2.degree.,
8.8.+-.0.2.degree., 10.5.+-.0.2.degree., 10.9.+-.0.2.degree.,
13.1.+-.0.2.degree., 17.4.+-.0.2.degree., 19.0.+-.0.2.degree.,
19.7.+-.0.2.degree., 20.3.+-.0.2.degree., 21.3.+-.0.2.degree.,
24.4.+-.0.2.degree. and 26.3.+-.0.2.degree.. Preferable is
5.3.+-.0.2.degree., 8.0.+-.0.2.degree., 8.8.+-.0.2.degree.,
13.1.+-.0.2.degree., 17.4.+-.0.2.degree., 19.0.+-.0.2.degree.,
20.3.+-.0.2.degree. and 26.3.+-.0.2.degree.. Further preferable is
5.3.+-.0.2.degree., 8.0.+-.0.2.degree., 13.0.+-.0.2.degree.,
19.0.+-.0.2.degree. and 20.3.+-.0.2.degree..
Test Example 1
The Solid Stability Test of Crystalline Solid
[0363] The type I crystal D about 1 g was put in a polyethylene bag
and tightened with a convex. This bag was further put in a
polyethylene bag and tightened with a convex in the same way. The
above sample of the same storage conditions was put together in a
metal can as a stability evaluation sample. The storage conditions,
storage period and test items are as follows.
There was no change in the appearance in the type I crystal D under
the following storage condition and strage period, and an increase
of content of its related substances was also not observed, and it
was confirmed to be a very stable.
(Storage Conditions)
[0364] Temperature: -20.+-.5.degree. C. or 5.+-.5.degree. C. [0365]
Light shielding [0366] Package form: double polyethylene bag,
convex, metal can [0367] Storage period: 0, 3, 6, 9, 12 months
(Measurement)
[0368] Using the type I crystal D stored at the above storage
conditions and storage period, after viewing the change in
appearance, the contents of the compound (IA) and the related
substances were measured by the following method.
Step 1: Preparation of a Sample Solution
[0369] About 40 mg of the sample was weighed precisely, and
dissolved in a sample dilution solvent to be exactly 25 mL. [0370]
5 mmol/L phosphate buffer/liquid chromatography acetonitrile
mixture (9:1) was used as the above sample dilution solvent was
used. Herein, water: 0.05 mol/L sodium dihydrogen phosphate test
solution: 0.05 mol/L disodium hydrogen phosphate reagent
mixture=18:1:1 (pH is about 7.1) was used as a phosphate
buffer.
Step 2: HPLC Measurement of Related Substances
[0371] The above sample solution was measured by liquid
chromatography under the following test condition to measure peak
areas of the compound (IA) and its related substances by the
automatic integration method.
(HPLC Condition)
[0372] Column: YMC-UltraHT Pro C18, .phi.2.0.times.100 mm, 2 .mu.m,
YMC [0373] Column temperature: 35.degree. C. [0374] UV detection
wavelength: 261 nm [0375] Mobile phase: [A] 0.1% trifluoroacetic
acid solution, [B] acetonitrile for liquid chromatography
Gradient Program
TABLE-US-00021 [0376] Time after addition Mobile phase A Mobile
phase B (minute) (vol %) (vol %) 0~0.6 95.fwdarw.90 5.fwdarw.10
0.6~3.3 90.fwdarw.88 10.fwdarw.12 3.3~4.5 88 12 4.5~7.0
88.fwdarw.87 12.fwdarw.13 7.0~12.4 87.fwdarw.65 13.fwdarw.35
12.4~12.5 65.fwdarw.95 35.fwdarw.5 12.5~15.0 95 5
[0377] Flow rate: 0.5 mL per minute (a retention time of the
compound (IA) about 5 minutes) The amount of related substances in
the sample was determined by using the following formula.
[0377] An amount of each related substance ( % ) = A i A T .times.
100 ##EQU00002## Total amount of related substances ( % ) = A i A T
.times. 100 ##EQU00002.2## [0378] A.sub.i: peak area of each
related substance except the p-toluenesulfonic acid [0379]
.SIGMA.A.sub.i: Total of peak area of each related substances
except the p-toluenesuofonic acid [0380] A.sub.T: Total of peak
area except system peak and p-toluenesulfonic acid
Step 3: HPLC Measurement of the Compound (IA)
(Preparation of a Standard Solution)
[0381] About 40 mg of a standard preparation of the type I crystal
D of the compound (IA) was weighed precisely, and dissolved in a
sample dilution solvent to be exactly 25 mL.
(Preparation of a Sample Solution)
[0382] About 40 mg of a sample equilibrated humidity was weighed
precisely, and was dissolved in a sample dilution solvent to be
exactly 25 mL.
[0383] 5 mmol/L phosphate buffer/liquid chromatography acetonitrile
mixture (9:1) was used as the above sample dilution solvent.
Herein, water: 0.05 mol/L sodium dihydrogen phosphate test
solution: 0.05 mol/L disodium hydrogen phosphate reagent
mixture=18:1:1 (pH is about 7.1) was used as a phosphate
buffer.
The above standard solution and sample solution was measured by
liquid chromatography under the following test condition to
determine a peak area of the compound (IA) by an automatic
integration method.
(HPLC Condition)
[0384] Column: YMC-UltraHT Pro C18, .phi.2.0.times.100 mm, 2 .mu.m,
YMC [0385] Column temperature: 35.degree. C. [0386] UV detection
wavelength: 261 nm [0387] Flow rate: 0.5 mL per minute (a retention
time of the compound (IA) about 5 minutes) [0388] mobile phase: [A]
0.1% trifluoroacetic acid solution, [B] acetonitrile for liquid
chromatography
Gradient Program
TABLE-US-00022 [0389] Time after addition Mobile phase A Mobile
phase B (minute) (vol %) (vol %) 0~0.6 95.fwdarw.90 5.fwdarw.10
0.6~3.3 90.fwdarw.88 10.fwdarw.12 3.3~4.5 88 12 4.5~7.0
88.fwdarw.87 12.fwdarw.13 7.0~12.4 87.fwdarw.65 13.fwdarw.35
12.4~12.5 65.fwdarw.95 35.fwdarw.5 12.5~15.0 95 5
The content of related substances in the sample was determined
using the following formula.
The content of the compound (IA)
(C.sub.30H.sub.34ClN.sub.7O.sub.10S.sub.2) on an anhydrous basis
(%)=M.sub.S/M.sub.T.times.C/1000.times.100/(100-W.sub.T).times.A.sub.T/A.-
sub.S.times.100 [0390] M.sub.S: weighed amount of the standard
preparation of the type I crystal of the compound (IA) (mg) [0391]
M.sub.T: weighed amount of the sample (mg) [0392] C: a content of
the standard sample of the type I crystal of the compound (IA)
(.mu.g/mg) [0393] W.sub.T: water equilibrated humidity of sample
(%) [0394] A.sub.S: a peak area of the compound (IA) obtained from
the standard solution [0395] A.sub.T: a peak area of the compound
(IA) obtained from the sample solution
Formulation Sample 1
[0396] The type I crystal D (123.1 g: 82.5 g as the compound (IA))
was suspended in 1155 g of water for injection, 8 wt % of sodium
hydrate aqueous solution was added to the suspension until reached
pH6 (added amount 159.2 g), and water for injection for weight
adjustment was added to the solution to prepare a solution of 50
mg/g as the compound (IA). In this case, it took 2 hours for
neutralizing dissolution. This solution was sterile filtered
through a PVDF membrane with 0.2 .mu.m of hole diameter. The
obtained filtrate was put into a glass vial, followed by
lyophilizing. As the condition of lyophilization, the primary
during was conducted by 1) cooling at 5.degree. C., 2) cooling for
1 hour at -5.degree. C., 3) freezing for 4 hours at -40.degree. C.,
4) -.degree. C. for 123 hours at 10 Pa vacuum pressure, and the
second drying was conducted at 5) 60.degree. C. for 6 hours at 10
Pa vacuum pressure to produce a lyophilized product.
* * * * *